InTechOpen uses cookies to offer you the best online experience. By continuing to use our site, you agree to our Privacy Policy.

 » "", book edited by , ISBN , Published: January 1, 1970 under CC BY-NC-SA 3.0 license. © The Author(s).

Chapter 5

The Impact of Vitamin D in Cancer

By Khanh Luong
DOI: 10.5772/55324

Article top

The Impact of Vitamin D in Cancer

Khanh vinh quoc Luong1 and Lan Thi Hoang Nguyen1

1. Introduction

The relationship between vitamin D and cancer has previously been reported in the literature. A systemic review and meta-analysis of prospective cohort studies revealed that a 20 nmol/L increase in the 25-hydroxyvitamin D3 (25OHD) levels was associated with an 8% lower mortality in the elderly population (Schöttker et al., 2012). Oncology patients had significantly lower mean serum vitamin D levels than non-cancer primary care patients from the same geographic region (Churilla et al., 2011). In a community oncology experience, vitamin D deficiency is widespread in cancer patients and correlates with advanced stage disease (Churilla et al., 2012). A high prevalent of vitamin D deficiency has been associated with head and neck cancer (Orell-Kotikangas et al., 2011), breast cancer (Crew et al., 2009; Peppone et al., 2012), vulvar cancer (Salehin et al., 2012), prostate cancer (Varsavsky et al., 2011), pancreatic cancer (Wolpin et al., 2011), gastric cancer (Ren et al., 2012), colon and rectal cancer (Tangrea et al., 1997), ovarian cancer (Lefkowitz et al., 1994), oral cavity and esophagus cancers (Lipworth et al., 2009), myelo-proliferative neoplasms and myelo-dysplastic syndromes (Pardanani et al., 2011), multiple myeloma (Ng et at., 2009), non-Hodgkin’s lymphoma (Drake et al., 2010), and chronic lymphocytic leukemia (Shamafelt et al., 2011). On the other hand, a serum 25OHD concentration of 25 nmol/L was associated with a 17% reduction in incidence of cancer, a 29% reduction in total cancer mortality, and a 45% reduction in digestive system cancer mortality (Giovannucci et al., 2006). Improving vitamin D status may also help lower the risk of colorectal cancer (Wu et al., 2011a). In a case-control study, a higher vitamin D intake is associated with a lower risk of esophageal squamous cell carcinoma (Launoy et al., 1998). A meta-analysis revealed that an increase of serum 25OHD by 50 nmol/L was associated with a risk reduction of 59% for rectal cancer and 22% for colon cancer (Yin et al., 2009). High 25OHD levels were associated with better prognosis in breast, colon, prostate cancer, and lung cancer relative to patients with lower 25OHD levels (Robsahm et al., 2004; Zhou et al., 2007). In a murine model, dietary vitamin D may play an important role as a preventive agent in androgen-insensitive human prostate tumor growth (Ray et al., 2012). The season in which patients were operated on seemed to have an effect on survival of patients undergoing resection of non-small cell lung cancer (Turna et al., 2012). The survival of patients who had surgery in winter was statistically significantly shorter than that of patients who underwent surgery in the summer. In Australia, prostate cancer mortality rates are inversely correlated with solar radiation exposure (Loke et al., 2011). Dietary vitamin D3 and calcitriol have been shown to demonstrate equivalent anticancer activity in mouse xenograft models of breast and prostate cancers (Swani et al., 2012). The combination of calcitriol and dietary soy resulted in substantially greater inhibition of tumor growth than the inhibition achieved with either agent alone in a mouse xenograft model of prostate cancer (Wang et al., 2012a). Soy diets alone caused a modest elevation in serum calcitriol. Vitamin D3 treatment significantly suppressed the viability of gastric cancer and cholangiocarcinoma cells and also had a synergistic effect with other anti-cancer drugs, such as paclitaxel, adriamycin, and vinblastine (Baek et al., 2011). The vitamin D analog, 19-Nor-2α-(3-hydroxypropyl)-1α,25-dihydroxyvitamin D3, is a potent cell growth regulator with enhanced chemotherapeutic potency in liver cancer cells (Chiang et al., 2011). Alphacalcidol, a vitamin D analogue, has been demonstrated significant antitumor activity in patients with low-grade non-Hodgkin’s lymphoma of the follicular, small-cleaved cell type (Raina et al., 1991). In patient with parathyroid cancer, vitamin D has been shown to prevent or delay the progression of recurrence (Palmieri-Sevier et al., 1993). In locally advanced or cutaneous metastatic breast cancer, topical calcipotriol treatment reduced the diameter of treated lesions that contained vitamin D receptor (VDR) (Bower et al., 1991). In a clinical trial, high-dose calcitriol decreased prostatic-specific antigen (PSA) levels by 50% and reduced thrombosis in prostate cancer patients (Beer et al., 2003 & 2006). In hepatocellular carcinoma, calcitriol and its analogs have been reported to reduce tumor volume, increase hepatocarcinoma cell apoptosis by 21.4%, and transient stabilize serum alpha-fetoprotein levels (Dalhoff et al., 2003; Luo et al., 2004; Morris et al., 2002). These findings suggested a relationship between vitamin D and cancer. In this chapter, we will discuss the role of vitamin D in cancer.

2. Genetic factors related to vitamin D and cancer

2.1. The Major Histocompatibility Complex (MHC) class II molecules

The major histocompatibility complex (MHC) class II molecules play an important role in the immune system and are essential in the defense against infection. The human MHC class II molecules are encoded by three different human leukocytic antigen (HLA) isotypes: HLA-DR, -DQ, and -DP. Studies have suggested that several genes within MHC region promote cancer susceptibility. A chimeric DR4 homozygous transgenic mouse line is reported to spontaneously develop diverse hematological malignancies at a high frequency (Raffegerst et al., 2009). Most of these neoplasms were highly similar to those found in human diseases. HLA-DR antigen expression was correlated with the histopathological type and to the degree of cell differentiation in cutaneous squamous cell carcinomas (Garcia-Plata et al., 1993). The DRB1*03 and DR-B1*13 alleles were significantly more frequent in patients with nasopharyngeal carcinoma compared with controls in southern Tunisia (Makni et al., 2010). The DR1 gene is strongly associated with thyroid carcinoma (Panza et al., 1982). The HLA-DR was also increased in poorly differentiated thyroid carcinoma, especially in the anaplastic type (Lindhorst et al., 2002). The DQA1*0102 and DPB1*0501 alleles were significantly more common in Chinese patients with hepatocellular carcinoma (HCC) (Donaldson et al., 2001). The frequency of DRB1*0404 allele was significantly higher in the gastric cancer group compared with the gastritis group in Koreans (Lee et al., 2009). However, the frequencies of the DRB1*0405 and DQB1*0401 alleles were increased in the Japanese patients with intestinal-type gastric cancer compared with controls (Ando et al., 2009). Somatic mutations affecting HLA class II genes may lead to loss of HLA class II expression due to the formation of microsatellites in unstable colorectal carcinomas (Michel et al., 2010). The DRB1*15 allele and the haplotype DRB1*15 DQB1*0602 were associated with human papillomavirus (HPV)-16 positive invasive cervical cancer in Mexican women (Hernández-Hernández et al., 2009). The DRB1*0410 allele was the susceptibility allele in Japanese patients with testicular germ cell carcinoma (Ozdemir et al., 1997). Furthermore, the frequencies of the DRB1*09 and DQB1*03 alleles were increased in patients with non-Hodgkin’s lymphoma and diffuse large B cell lymphoma compared with normal controls (Choi et al., 2008). The frequencies of the DRB1*04 and DRB1*15 alleles were significantly higher in Turkish children with acute leukemia compared with controls (Ozdilli et al., 2010). The DRB1*16 allele was a marker for a signignificant risk of chronic myelogenous leukemia in Eastern Canada (Naugler and Liwski, 2009). The DRB1*04 and DRB5 alleles are associated with disease progression in Iranian patients with chronic lymphocytic leukemia (Hojattat-Farsangi et al., 2008). On the other hand, calcitriol is known to stimulate phagocytosis and suppress MHC class II antigen expression in human mononuclear phagocytes (Tokuda et al., 1992 & 1996), thereby preventing antigen-specific T cell proliferation. In addition, calcitriol exerts effects that opposes the effect of IL-4 on MHC class II antigen expression in human monocytes (Xu et al., 1993) and specifically modulates human monocyte phenotype and function by altering HLA-DR antigen expression and antigen presentation, while leaving lytic function intact (Rigby et al., 1990). Calcitriol also decreases interferon-γ-induced HLA-DR antigen expression in normal and transformed human keratinocytes (Tamaki et al., 1990-1991 & Tone et al., 1991) and reduces the levels of HLA-DR mRNA in cultured epithelial tumor cell lines (Tone et al., 1993). In addition, 1α-calcidol significantly modulates the expression of HLA-DR in human peripheral blood monocytes (Scherberich et al., 2005). These findings suggest that calcitriol may have an effect on cancer by suppressing the expression of MHC class II antigens.

2.2. Vitamin D Receptor (VDR)

The expression of VDR in a variety of cell lines, coupled with increased evidence of VDR involvement in cell differentiation, inhibition of cellular proliferation and angiogenesis in many tumor types, suggest that vitamin D plays a role in cancer (Luong and Nguyen, 2010 & Lương and Nguyễn, 2012). VDR ablation is associated with ductal ectasia of the primary mammary ducts, loss of secondary and tertiary branches and atrophy of the mammary fad pad (Welsh et al., 2011). Breast cancer patients with high VDR expression showed significant better in progression-free survival and overall survival than patients with moderate/negative VDR expression scores (Ditch et al., 2012). Certain allelic variations in the VDR may also be genetic risk factors for developing tumors. There are five important common polymorphisms within the VDR gene region that are likely to exert functional effects on VDR expression. The anti-carcinogenic potential of vitamin D might be mediated by VDR expression. The association between plasma 25OHD levels and colorectal adenoma was modified by the TaqI polymorphism of the VDR gene (Yamaji et al., 2011). There is a significant association between single nucleotide polymorphisms (SNPs) in the VDR gene and vitamin D intake in African Americans with colorectal cancer (Kupfer et al., 2011). The BsmI polymorphism of the VDR gene also modified the association between dietary vitamin D intake and breast cancer (Rollison et al., 2012). The AA genotype of VDR is reported to be associated with colorectal cancer, with a stronger association in female patients (Mahmoudi et al., 2012). The FokI and BsmI genotypes of VDR gene are implicated in the pathogenesis of renal cell carcinoma (RCC) in a North Indian population (Arjumand et al., 2012). Altered VDR expression was associated with RCC carcinogenesis via the expression of epithelial Ca2+ channel transient receptor potential vanilloid subfamily 5 and 6 (TRPV5/6) (Wu et al., 2011b). There is a significant association between shorter progression-free survival time in patients with head and neck squamous cell carcinoma and the FokI TT genotype, as well as the Cdx2-FoxI-ApaI haplotype (Hama et al., 2011). In Spanish children, osteosarcoma patients showed a significantly higher frequency of the Ff genotype of the FokI VDR gene than the control group (Ruza et al., 2003). In a German population, the AaTtBb genotype of the VDR gene is associated with basal cell carcinoma risk, whereas the aaTTbb genotype is found at a high frequency in both basal cell carcinomas and cutaneous squamous cell carcinomas compared with controls (Köststner et al., 2012). In a systematic review, TaqI, BsmI and FokI polymorphisms of the VDR gene were found to be associated with malignant melanoma (Denzer et al., 2011). Furthermore, the presence of specific VDR BsmI and TaqI alleles was associated with a higher C-reactive protein (CRP) level in cancer patients with cachectic syndrome (Punzi et al., 2012). In another prospective study, plasma 25OHD levels and common variation among several vitamin D-related genes (CYP27A1, CYP2R1, CYP27B1, CYP24A1, GC, RXRA, and VDR) were associated with lethal prostate cancer risk (Shui et al., 2012). Slattery et al. (2009) examined genetic variants that are linked to the pathway that contribute to colon cancer. They revealed that FoxI VDR polymorphism was associated with CpG Island methylator phenotype (CIMP) positive/Ki-ras mutated tumors, whereas the Poly A and Cdx2 VDR polymorphisms were associated only with Ki-ras mutated tumors.

2.3. MicroRNA (miRNA)

MiRNAs are endogenous noncoding RNAs that regulate gene expression through the translational repression or degradation of target mRNA (Bartel, 2004). Aberrant miRNA expression has been well characterized in cancer (Lu et al., 2005). Circulating miRNAs are suggested to be diagnostic and prognostic markers in breast cancer (Cortez et al., 2012). Circulating miRNA-125b expression is associated with chemotherapeutic resistance of breast cancer (Wang et al., 2012b). Several miRNAs are found to share 125b complementarity with a sequence in the 3’-unstranslated region of human VDR mRNA. The overexpression miRNA-125b significantly decreased the endogenous VDR protein level in human breast adenocarcinoma cells lines (MCF-7) to 40% of the control (Mohri et al., 2009). This miRNA is down-regulated in cancer tissue and causes high CYP24 protein expression, which catalyzes the inactivation of calcitriol (Komagata et al., 2009). Stress induced by serum starvation caused significant alteration in the expression of multiple miRNAs including miRNA-182, but calcitriol effectively reversed this alteration in breast epithelial cells (Peng et al., 2010). Vitamin D3 up-regulated protein 1 (VDUP1) is regulated by miRNA-17-5p at the post-transcriptional levels in senescent fibroblasts (Zhuo et al., 2010). VDUP1 expression is increased in cancer cells (Takahashi et al., 2002; Dutta et al., 2005). In melanoma cell lines, the endogenous VDR mRNA level is inversely associated with expression of miRNA-125b (Essa et al., 2010), and calcitriol also reduced the miRNA-27b expression in these cell lines. In human colon cells, calcitriol induced miRNA-22 and may contribute to its antitumor action against this neoplasm (Alvarez-Diaz et al., 2012). Fifteen miRNAs are also differentially regulated by calcitriol in prostate cancer cells (LNCaP) (Wang et al 2011a). Furthermore, calcitriol regulated miRNA-32 and miRNA-181 expressions in human myeloid leukemia cells (Gocek et al., 2011; Zimmerman et al., 2011; Wang et al., 2009a).

2.4. Renin-Angiotensin System (RAS)

The primary function of the renin-angiotensin system (RAS) is to maintain fluid homeostasis and regulate blood pressure. The angiotensin converting enzyme (ACE) is a key enzyme in the RAS and converts angiotensin (AT) I to the potent vasoconstrictor AT II (Johnston, 1994). The local RAS may influence tissue angiogenesis, cellular proliferation, apoptosis, and inflammation (Deshayes and Nahmias, 2005). Epidemiological and experimental studies suggested that the RAS may contribute to the paracrine regulation of tumor growth. The renin levels are elevated in patients with liver cirrhosis and HCC and positively correlated with α-fetoprotein (Lotfy et al., 2010). The over-expression of ACE is reported in extrahepatic cholangiocarcinoma (Beyazit et al., 2011), leukemic myeloid blast cells (Aksu et al., 2006), and macrophages in the lymph nodes of Hodgkin’s disease patients (Koca et al., 2007). The AT II receptors were also expressed in all human gastric cancer lines (Huang et al., 2008), pre-malignant and malignant prostate cells (Louis et al., 2007), human lung cancer xenografts (Feng et al., 2011a), and ovarian cancer (Ino et al., 2006). The RAS mutation in codon 61 was the most common genetic alteration in poorly differentiated thyroid carcinomas (Volante et al., 2009). The ACE I/D polymorphism is a possible target for developing genetic markers for breast cancer in Brazilian women (Alves Corrêa et al., 2009). The ACE I/D polymorphisms play an important role in breast cancer risk and disease-free survival in Caucasian postmenopausal women (González-Zuloeta Ladd et al., 2012). Carriers of the high-activity DD genotype had an increased risk of breast cancer compared with low activity II/ID genotype carriers (van der Knaap et al., 2008). The DD genotype was associated with patients with an aggressive stage of prostate cancer (Wang et al., 2011b). ACE2 expression was decreased in non-small-cell lung cancer and pancreatic ductal adenocarcinoma in which AT II levels were higher than those in controls (Feng et al., 2010; Zhou et al., 2009). ACE2 has been suggested as a potential molecular target for pancreatic cancer therapy (Zhou et al., 2011). The AT II concentration in gastric cancer region was significantly higher than those of normal region (Kinoshita et al., 2009). Furthermore, AT II receptor blockers (ARB) suppress the cell proliferation effects of AT II in breast cancer cells (Du et al., 2012). The addition of ACE inhibitor or ARB to platinum-based first line chemotherapy contributed to prolong survival in patients with advanced lung cancer (Wilop et al., 2009) and affected the prognosis of advanced pancreatic cancer patients receiving gemcitabine (Nakai et al., 2010). The RAS inhibitors also improved the outcome of sunitinib treatment in metastatic renal cell carcinoma (Keizman et al., 2011). On the other hand, the administration of ACE inhibitors in patients with the ACE DD genotype has been shown to decrease the level of calcitriol required (Pérez-Castrillón et al., 2006). In a hypertensive Turkish population, the presence of the ACE D allele, which correlates negatively with serum 25OHD levels, is linked to a higher left ventricular mass index value and elevated ambulatory blood pressure measurements (Kulah et al., 2007). In addition, genetic disruption of the VDR gene resulted in overstimulation of the RAS with increased renin and angiotensin II production, which lead to high blood pressure and cardiac hypertrophy. However, treatment with captopril reduced cardiac hypertrophy in VDR-knockout mice (Xiang et al., 2005), suggesting that calcitriol may function as an endocrine suppressor of renin biosynthesis. Moreover, calcitriol suppresses renin gene transcription by blocking the activity of the cyclic AMP response element in the renin core promoter (Yuan et al., 2007) and decreases ACE activity in bovine endothelial cells (Higiwara et al., 1988).

2.5. Toll-Like Receptor (TLR)

Toll-like receptors (TLRs) are a group of glycoproteins that functions as surface trans-membrane receptors and are involved in the innate immune responses to exogenous pathogenic microorganisms. Substantial evidence exists for an important role of TLRs in the pathogenesis and outcomes of cancer. TLR2 expression was significantly higher in sporadic colorectal cancerous tissue than in non-cancerous tissue (Nihon-Yanagi et al., 2012). The TLR5 play an important role in tumor progression of gastric cancer (Song et al., 2011). The TLR7 and TLR9 showed high expression in laryngeal carcinoma cells (Shikora et al., 2010). The over-expression of TLR9 was reported oral squamous cell carcinoma (Min et al., 2011), esophageal squamous cell carcinoma (Takala et al., 2011), and breast cancer cells (Qiu et al., 2011; Sandholm et al., 2012). The expression levels of TLR1, TLR2, TLR4, TLR5, TLR6, TLR8, and TLR10 are significantly higher in the human renal carcinoma cell line (780-6) than those in normal renal cell (HK-2) line (Yu et al., 2011). Chronic lymphocytic leukemia cells express all TLRs expressed by normal activated B cells, with a high expression of TLR9 and CD180 and an intermediate expression of TLR1, TLR6, and TLR10 (Arvaniti et al., 2011). The TLR4 polymorphisms are reported in patients with the risk of prostate cancer (Kim et al., 2012), head and neck squamous cell carcinomas (Bergmann et al., 2011), HCC (Minmin et al., 2011), and colon cancer (Eyking et al., 2011). Furthermore, multiple SNPs in TLR2 and TLR4 were associated with colon cancer survival (Slattery et al., 2012). On the other hand, vitamin D deficiency increases the expression of hepatic mRNA levels of TLR2, TLR4, and TLR9 in obese rats (Roth et al., 2011). However, calcitriol suppresses the expression of TLR2 and TLR4 protein and mRNA in human monocytes and triggers hypo-responsiveness to pathogen-associated molecular patterns (Sadeghi et al., 2006). Calcitriol has also been shown to down-regulate intracellular TLR2, TLR4 and TLR 9 expression in human monocytes (Dickie et al., 2010). TLR activation results in the expression of the VDR and 1α-vitamin D hydroxylase in human monocytes (Liu et al., 2006). Additionally, calcitriol can cause the vitamin D-induced expression of cathelicidin in bronchial epithelial cells (Yim et al., 2007) and may enhance the production of cathelicidin LL-37 (Rivas-Santiago et al., 2008). The addition of a VDR antagonist has also been shown to inhibit the induction of cathelicidin mRNA by more than 80%, thereby reducing the protein expression of this antimicrobial agent by approximately 70% (Yim et al., 2007). Cathelicidin was abundant in tumor-infiltrating NK1.1+ cells in mice. Cathelicidin knockout mice (Camp-/-) permitted faster tumor growth than wild type controls; NK cells derived from Camp-/- mice showed impaired cytotoxic activity toward tumor targets compared with wild-type mice (Büchau et al., 2010). The human cathelicidin LL-37, which inhibits gastric cancer cell proliferation, is down-regulated in gastric adenocarcinomas (Wu et al., 2010). Gastrointestinal cancer cells lacked LL-37 expression; Cathelicidin expression is modulated by histone-deacetylase (HDAC) inhibitors in various gastrointestinal cells, including gastric and hepatocellular cells (Schauer et al., 2004). HDAC inhibitors enhance the acetylation of core proteins, which is linked to the formation of transcriptionally active chromatin in various cells. The expression of the LL-37/hCAP-18 gene was also reduced in some leukemia cells (Yang et al., 2003). In patients with acute myeloid leukemia, there was a marked reduction of LL-37/hCAP-18 expression in the peripheral blood compared with the level in healthy donors (An et al., 2005). In myeloid cells, cathelicidin gene is a direct target of the VDR and is strongly up-regulated by calcitriol (Gombart et al., 2005). The combination of TLR ligands (CpG oligodeoxynucleotides, CpG-ODN) LL-37 generated significantly better therapeutic tumor effects and enhanced survival in murine ovarian tumor-bearing mice compared with CpG-ODN or LL-37 alone (Chuang et al., 2009).

3. Role of vitamin D and its analog in cancer

3.1. The bacillus Calmette-Guerin (BCG) vaccination

The BCG vaccine was developed to provide protection against tuberculosis and has also been demonstrated to offer protection against cancer. The combination of BCG and ionizing radiation resulted in the induction of autophagy in colon cancer cells (Yuk et al., 2010). Intravesical BCG therapy has been demonstrated to reduce the recurrence rate and the risk of progression to muscle-invasive disease in patients with superficial bladder tumors (Herr et al., 1988). The BCG vaccination significantly prolongs the survival of patients with a malignant melanoma after initial surgical removed (Kölmel et al., 2005) and improved survival rates in patients with resected lung cancer (Repin, 1992). BCG inoculation delayed the tumor growth and prolonged the survival time in nude mice with leukemia (Wang et al., 2011c). BCG vaccination reduced the risk of lymphomas in a Danish population (Villumsen et al., 2009) and demonstrated to reduce the mortality, morbidity, and frequency of myeloic and chronic leukemia in children (Ambrosch et al., 1981). On the other hand, BCG-vaccinated infants are almost 6 times more likely to have sufficient vitamin D concentrations than unvaccinated infants 3 months after BCG vaccination, and this association remains strong even after adjusting for season, ethnic group and sex (Lalor et al., 2011). Among the vaccinated group, there was also a strong inverse correlation between the IFN-γ response to M. tuberculosis PPD and vitamin D concentration; infants with higher vitamin D concentrations had lower IFN-γ responses. Similarly, tuberculosis in cattle usually presents with a rapid transient increase in serum calcitriol within the first two weeks following infection (Rhodes et al., 2003). 1,25OHD-positive mononuclear cells were later identified in all of the tuberculous granulomas. During tuberculosis infection, alveolar macrophage-produced calcitriol plays a beneficial role by limiting inflammation-mediated tissue injury, potentiating NO production by stimulated monocytes/macrophages, inhibiting INF-γ production by stimulated CD4+ cells, and suppressing the growth of M. tuberculosis (Ametaj et al., 1996; Rockett et al., 1998).

3.2. Matrix Metalloproteinase (MMPs)

MMPs are proteolytic enzymes responsible for extracellular matrix remodeling and the regulation of leukocyte migration through the extracellular matrix, which is an important step in inflammatory and infectious pathophysiology. MMPs are produced by many cell types including lymphocytes, granulocytes, astrocytes and activated macrophages. The MMP-1 expression is linked to sarcoma cell invasion (Garamszegi et al., 2011). MMP-2 expression is increased in gastric cancer cells (Partyka et al., 2012) and colorectal cancer (Dong et al., 2011). MMP-9 is expressed in many cancer cells, such as those associated with non-small-cell lung cancer (Peng et al., 2012), ovarian cancer invasion and metastasis (Zhang et al., 2011a), glioblastoma multiforme (Yan et al., 2011), and adamantinous craniopharyndioma (Xia et al., 2011). The MMP-2 and MMP-9 secreted by leukemic cells increase the permeability of blood brain barrier of the CNS by disrupting tight junction proteins (Feng et al., 2011b). In gastric cancer, MMP-2 and MMP-9 play an important role in tumor invasion and metastasis (Parsons et al., 1998). The risks for the development of hypophyseal adenoma and cervical neoplasia are greater in patients with MMP-1 polymorphisms (Altaş et al., 2010; Tee et al., 2012) than those with the wild-type allele. The MMP-2 polymorphism contributed to prostate cancer susceptibility in North India (Srivastava et al., 2012) and to the clinical outcome of Chinese patients with non-small cell lung cancer treated with first-line, platinum-based chemotherapy (Zhao et al., 2011). The MMP-7 polymorphisms are associated with esophageal squamous cell carcinoma and colorectal cancers (Manzoor et al., 2011; Dziki et al., 2011). The SPNs in the MMP-2 and MMP-9 region are associated with susceptibility to head and neck squamous cell carcinoma in an Indian population (Chaudhary et al., 2011). The SNPs of genes encoding MMPs (-1, -2, -3, -7, -8, -9, -12, -13, and -21) are related to breast cancer risk, progression, and survival (Wieczorek et al., 2012). Based on meta-analysis studies, the MMP-2 allele (-1306T) is a protective factor for digestive cancer risk (Zhang and Ren, 2011), the MMP-9 polymorphism is associated with a lower risk of colorectal cancer (Zhang et al., 2012a), and polymorphisms in the promoter regions of MMP-1, -3, -7, and -9 are associated with metastasis in some cancers (Liu et al., 2012). On the other hand, VDR-knock-out mice were shown to have an influx of inflammatory cells, phospho-acetylation of NF-κв, and up-regulated expression of MMP-2, MMP-9, and MMP-12 in the lung (Sundar et al., 2011). The VDR TaqI polymorphism is associated with decreased production of TIMP-1, a natural inhibitor of MMP-9 (Timms et al., 2002). In addition, calcitriol modulates tissue MMP expression under experimental conditions (Dean et al., 1996), down-regulates MMP-9 levels in keratinocytes, and may attenuate the deleterious effects of excessive TNF-α-induced proteolytic activity associated with cutaneous inflammation (Bahar-Shang et al., 2010). Calcitriol decreased the invasive properties of breast carcinoma cells and decreased MMP-9 levels in association with the increased levels of the tissue inhibitor of MMP-1 activity (Koli and Keshi-Oja, 2000). Calcitriol also inhibits endometrial cancer cell growth and is associated with decreased MMP-2 and MMP-9 expression (Nguyen et al., 2011). Moreover, calciferol, calcitriol, and vitamin D analogs decreased MMP-2 and MMP-9 activities and inhibited prostate cancer cell invasion (Tokar and Webber, 2005; Schartz et al., 1997; Iglesias-Gato et al., 2011; Stio et al., 2011). A vitamin D analog has also been reported to reduce the expression of MMP-2, MMP-9, vascular endothelial growth factor (VEGF) and PTH-related peptide in Lewis lung carcinoma cells (Nakagawa et al., 2005). Taken together, these studies suggest that calcitriol may play an important role in the pathological processes in cancer by down-regulating the level of MMPs and regulating the level of TIMPs.

3.3. Wnt/β-catenin

The Wnt/β-catenin signaling pathway plays a pivotal role in the regulation of cell growth, cell development and the differentiation of normal stem cells. Wnt/β-catenin signaling is implicated in many human cancers, including gastrointestinal cancer, gastric cancer, colon cancer, melanoma, HCC, endometrial carcinoma, ovarian carcinoma, cervical cancer, papillary thyroid carcinoma, renal cell carcinoma, prostate cancer, parathyroid carcinoma, and hematological malignancies (White et al., 2012; Nuñez et al., 2011; Polakis, 2000; Li et al., 2012; Yoshioka et al., 2012; Guturi et al., 2012; Bulut et al., 2011; Gilber-Sirieix et al., 2011; Ueno et al., 2011; Svedlund et al., 2010; Ge and Wang, 2010). Calcitriol inhibits β-catenin transcriptional activity by promoting VDR binding to β-catenin and the induction of E-cadherin expression (Palmer et al., 2001). Paricalcitol, a vitamin D analog, suppressed β-catenin-mediated gene transcription and ameliorated proteinuria and kidney injury in adriamycin nephropathy (He et al., 2011). Most VDR variants fail to activate the vitamin D-responsive promoter and also fail to bind β-catenin or regulate its activity (Byers and Shah, 2007). VDR depletion enhances Wnt/β-catenin signaling and the tumor burden in colon cancer (Larriba et al., 2011). The action of cacitriol on colon carcinoma cells depends on the dual action of VDR as a transcription factor and a nongenomic activator of RhoA-ROCK and p38MAPK-MSK1, which are required for the inhibition of the Wnt/β-catenin signaling pathway and cell proliferation (Ordóñez-Morán et al., 2008). The DICKKOFF-4 gene induces a malignant phenotype, promotes tumor cell invasion, and angiogenesis in colon cancer cells and is repressed by calcitriol (Pendás-Franco et al., 2008a); whereas DICKKOFF-1 gene acts as a tumor suppressor in human colon cells and is up-regulated by calcitriol (Aguilera et al., 2007; Pendás-Franco et al., 2008b). The transcription factor TCF-4 acts as transcriptional repressor in breast and colorectal cancer cell growth. The TCF-4 and β-catenin binding partner are indirect targets of the VDR pathway. In the VDR knockout mouse, TCF-4 is decreased in the mammary gland when compared with a wild-type mouse. In addition, calcitriol increases TCF-4 RNA and protein levels in several human colorectal cancer cell lines (Beildeck et al., 2009). Furthermore, the Snail1 gene is associated with gastric cancer, melanoma, breast cancer, HCC, and colon carcinoma. Calcitriol inhibits the Wnt/β-catenin signaling pathway and is abrogated by Snail1 in human colon cancer cells (Larriba et al., 2007).

3.4. The Mitogen-Activated Protein Kinase (MAPK) pathways

The MAPK pathways provide a key link between the membrane bound receptors that receive these cues and changes in the pattern of gene expression, including the extracellular signal-regulated kinase (ERK) cascade, the stress activated protein kinases/c-jun N-terminal kinase (SAPK/JNK) cascade, and the p38MAPK/RK/HOG cascade (Hipskind and Bilbe, 1998). In human colon cancer cells, calcitriol increases cytosolic Ca2+ concentration and transiently activates RhoA-ROCK, and then activates the p38MAPK-MSK signaling pathway (Ordóñez-Morán et al., 2008). In breast cancer cells, the MARK (JNK and p38) signaling pathway involved in calcitriol-induced breast cell death (Brosseau et al., 2010) and potentiated the cytotoxic action of calcitriol and TNF-α (Weitsman, et al., 2004). In murine squamous cell carcinoma cells, vitamin D induced apoptosis and selective induction of caspase-dependent MEK cleavage (McGuire et al., 2001). In an ovarian cancer animal model, vitamin D induced cell death and is mediated by the p38MAPK signaling pathway (Lange et al., 2010). In human promyeloblastic leukemia cells (HL60), vitamin D derivatives had anti-proliferative activity and activated MAPK signaling pathways (Ji et al., 2002). In human acute myeloid leukemia cells, calcitriol-induced differentiation is enhanced by the activation of MAPK signaling pathways (Zhang et al., 2011b).

3.5. The Prostaglandins (PGs)

Prostaglandins (PGs) play a role in inflammatory processes, and cyclooxygenase (COX) participates in the conversion of arachidonic acid in PGs. A variety studies have shown that prostaglandin signaling stimulates cancer cell growth and cancer progression. The regulation of PG metabolism and biological actions contribute to its anti-proliferation effects in prostate cells and calcitriol has been reported to regulate the expression of several key genes involved in the PG pathway, resulting in decreased PG synthesis (Moreno et al., 2005). The expression of the COX-2 gene is significantly increased in human gastric adenocarcinoma tissues compared with adjuvant normal gastric mucosal specimens (Ristimäki et al., 1997). There is inversely association between elevated COX-2 levels and decreased VDR expression in patients with breast and ovarian cancers compared with healthy women (Cordes et al., 2012). Calcitriol differentiated the human leukemic cell line (HL-60) and metabolized exogenous arachidonic acid to both COX products (predominantly thromboxane B2 and PG E2) and lipoxygenase products, including leukotriene B4 (Stenson et al., 1988). In a mouse xenograft model of prostate cancer, the combination of cacitriol and dietary soy enhanced cacitriol activity in regulating target gene expression and increased the suppression of PG synthesis and signaling, such as COX-2, 15-hydroxyprostaglandin dehydrogenase (15-PGDH), and PG receptors. (Wang et al., 2012a). Calcitriol and its analogs have also been shown to selectively inhibit the activity of COX-2 (Aparna et al., 2008), and an inverse correlation exists between the expression of PG-metabolizing enzymes and reduced VDR expression in malignant breast cell lines (Thill et al., 2012). Taken together, these findings suggest that vitamin D may play a role in modulating the inflammatory process in cancer.

3.6. Oxidative stress

Reactive oxygen species (ROS) play a major role in various cell-signaling pathways. ROS activates various transcription factors and increases in the expression of proteins that control cellular transformation, tumor cell survival, tumor cell proliferation and invasion, angiogenesis, and metastasis. ROS has an important role in the initiation and progression of many cancers (Gupta et al., 2012; Marra et al., 2011; Zhang et al., 2011c; Wang et al., 2011c; Rogalska et al., 2011; Gupta-Elera et al., 2012). Single nucleotide polymorphisms of antioxidant defense genes may significantly modify the functional activity of the encoded proteins. Women with genetic variability in the iron-related oxidative stress pathways may be at increased risk of post-menopausal breast cancer (Hong et al., 2007). The ala variant of superoxide dismutase (SOD) is associated with a moderately increased risk of prostate cancer (Woodson et al., 2003). Based on meta-analysis studies, manganese SOD (MnSOD) polymorphisms may contribute to cancer development (Val-9Ala) (Wang et al., 2009b), prostate cancer susceptibility (Val-16Ala) (Mao et al., 2010), but not to breast cancer susceptibility (Val-16Ala) (Ma et al., 2010a). Calcitriol can also protect nonmalignant prostate cells from oxidative stress-induced cell death through the prevention of reactive oxygen species (ROS)-induced cellular injuries (Bao et al., 2008). Vitamin D metabolites and vitamin D analogs have been reported to induce lipoxygenase mRNA expression, lipoxygenase activity and ROS in a human bone cell line (Somjen et al., 2011). Vitamin D can also reduce the extent of lipid peroxidation and induce SOD activity in the hepatic anti-oxidant system of rats (Sardar et al., 1996). Moreover, the activation of macrophage 1α-hydroxylase results in an increase in 1,25OHD, which inhibits iNOS expression and reduces nitric oxide (NO) production by LPS-stimulated macrophages (Chang et al., 2004). This calcitriol production by macrophages may provide protection against the oxidative injuries caused by the NO burst. Calcitriol is known to inhibit LPS-induced immune activation in human endothelial cells (Equil et al., 2005), and calcitriol has also been shown to enhance intracellular glutathione pools and significantly reduce the nitrite production induced by the LPS (Garcion et al., 1999). Furthermore, overproduction of ROS induces DNA damage and leads to carcinogenesis. In the mouse colon, there was an inverse relationship between VDR levels and colonic hyperproliferation; the expression of 8-hydroxy-2’-deoxyguanosine (8-OHdG), a maker of oxidative DNA damage, significantly increased with complete loss of VDR (Kállay et al., 2002). Vitamin D decrease 8-OHdG by 22% in the normal human colorectal mucosa (Fedirko et al., 2012). Calcitriol contributes to a reduction of the DNA intensify replication stress in lymphocytes (Halicka et al., 2012). In addition, vitamin D3 up-regulated protein 1(VDUP1) is a regular for redox signaling and stress-mediated diseases (Chung et al., 2006). Taken together, these findings suggest that vitamin D modulates oxidative stress in cancer.

4. The use of vitamin D in cancer treatment

A number of clinical trials have used vitamin D3 and calcitriol alone or in combination with anti-tumor agents. Most preclinical suggest that that the optimal anti-tumor effect of calcitriol and other analogs is seen with the administration of high dose calcitriol on intermittent schedule. A small number of single agent trials utilizing vitamin D3 and calcitriol hace been conducted with limited success.

4.1. Vitamin D3 trials

Fifteen patients were given 2,000 IU (50 microg) of cholecalciferol daily and monitored prospectively every 2-3 mo. There was a statistically significant decrease in the rate of PSA rise after administration of cholecalciferol compared with that before cholecalciferol. The median PSA doubling time increased from 14.3 months prior to commencing cholecalciferol to 25 months after commencing cholecalciferol. Fourteen of 15 patients had a prolongation of PSA doubling time after commencing cholecalciferol (Woo et al., 2005). Breast cancer patients with bone metastases received 10,000 IU of vitamin D3 daily for 4 months. There was a significant reduction in the number of sites of pain (Amir et al., 2010). Arlet al. (2012) reported on an unexpected observation of a spectacular 13-month remission of chronic lymphocytic leukemia after the administration of cholecalciferol in an elderly patient. Dietary vitamin D3 and calcitriol have been shown to demonstrate equivalent anticancer activity in mouse xenograft models of breast and prostate cancers (Swani et al., 2012).

4.2. Calcitriol trials — Single agent

In a clinical trial, high-dose calcitriol decreased prostatic-specific antigen (PSA) levels by 50% and reduced thrombosis in prostate cancer patients (Beer et al., 2003 & 2006). In hepatocellular carcinoma, calcitriol and its analogs have been reported to reduce tumor volume, increase hepatocarcinoma cell apoptosis by 21.4%, and transient stabilize serum alpha-fetoprotein levels (Dalhoff et al., 2003; Luo et al., 2004; Morris et al., 2002). The vitamin D analog, 19-Nor-2α-(3-hydroxypropyl)-1α,25-dihydroxyvitamin D3, is a potent cell growth regulator with enhanced chemotherapeutic potency in liver cancer cells (Chiang et al., 2011). Alphacalcidol, a vitamin D analogue, has been demonstrated significant antitumor activity in patients with low-grade non-Hodgkin’s lymphoma of the follicular, small-cleaved cell type (Raina et al., 1991). In patient with parathyroid cancer, vitamin D has been shown to prevent or delay the progression of recurrence (Palmieri-Sevier et al., 1993). Treatment with paricalcitol inhibited gastric cancer cell growth and peritoneal metastatic gastric cancer volume was significantly lower in paricalcitol treated mice (Park et al., 2012). Calcitriol treatment of breast cancer cell lines led to significantly fewer inflammatory breast cancer experimental metastases as compared to control (Hillyer et al., 2012).

4.3. Calcitriol trials — In combination

Calcitriol additively or synergistically potentiates the antitumor of other types of chemotherapeutic agents. Calcitriol enhances cellular sensitivity of human colon cancer cells to 5-fluorouracil (Liu et al., 2010). Combination of calcitriol and cytarabine prolonged remission in elderly patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) (Slapak et al., 1992; Ferrero, et al., 2004). A renal cell carcinoma patient with multiple bone metastases that were almost completely resolved after treatment with vitamin D and interferon-α (Fujioka et al., 1988). In a prospective study, a combination of active vitamin D and α- interferon has shown to be effective in patients with metastatic renal cell carcinoma (Obara et al., 2008). Calcitriol promotes the anti-proliferative effects of gemcitabine and cisplatin in human bladder cancer models (Ma et al., 2010b), and also potentiates antitumor activity of paclitaxel and docetaxel (Hershberger et al., 2001; Ting et al. 2007). A phase II study showed that high-dose calcitriol with docetaxel may increase time to progression in patients with incurable pancreatic cancer when compared with docetaxel monotherapy (Blanke, 2009).Vitamin D3 treatment significantly suppressed the viability of gastric cancer and cholangiocarcinoma cells and also had a synergistic effect with other anti-cancer drugs, such as paclitaxel, adriamycin, and vinblastine (Baek et al., 2011). In locally advanced or cutaneous metastatic breast cancer, topical calcipotriol treatment reduced the diameter of treated lesions that contained vitamin D receptor (VDR) (Bower et al., 1991). Calcitriol potentiates both carboplatin and cisplatin-mediated growth inhibition in breast and prostate cancer cell lines (Cho et al., 1991; Moffatt et al., 1999). Tamoxifen and calcitriol or its analog used together to enhance growth inhibition in breast cancer cells than either agent alone (Vink-van Wijngaarden et al., 1994). Cacitriol sensitizes breast cancer cells to doxorubicin through the inhibition of the expression and activity of cytoplasmic antioxidant enzyme (Ravid et al., 1999). Calcitriol may increase cisplatin sensitivity in chemotherapy-resistant testicular germ cell cancer-derived cell lines (Jørgensen et al., 2012). Combination of retinoic acid and vitamin D analog exert synergistic growth inhibition and apoptosis induction on hepatocellular cancers cells (Zhang et al., 2012b). The combination of calcitriol and dietary soy resulted in substantially greater inhibition of tumor growth than the inhibition achieved with either agent alone in a mouse xenograft model of prostate cancer (Wang et al., 2012a).

5. Conclusion

Vitamin D has a role in the prevention and treatment of cancer. Genetic studies have provided the opportunity to determine what proteins link vitamin D to the pathology of cancer. Vitamin D also exerts its effect on cancer via non-genomic mechanisms. As a result, it is imperative that vitamin D levels in patients with cancer be followed. Many studies use the relationship between serum PTH and 25OHD to define the normal range of serum 25OHD. According to the report on Dietary Reference Intakes for vitamin D and calcium by the Institute of Medicine (IOM), persons are at risk of deficiency at serum 25OHD levels less than 30 nmol/L. Saliba et al. (2011) suggested that a 25OHD threshold of 50 nmol/L is sufficient for PTH suppression and prevention of secondary hyperparathyroidism in persons with normal renal function. It is necessary to check serum 25OHD3 and parathyroid hormone (PTH) status in cancer patients. Serum levels of PTH have been reported to correlate with PSA levels and colorectal cancer (Skinner & Schwartz, 2009; Charalampopoulos et al., 2010). Some authors proposed that, in patients with normal calcium levels, the serum 25OHD3 levels should be stored to > 55ng/ml in cancer patients (colon, breast, and ovary) (Garland et al., 2007). Calcitriol, 1,25OHD3, is best used for cancer treatment, because of its active form of vitamin D3 metabolite, suppression of PTH levels (acted as cellular growth factor), and their receptors presented in most of human cells. However, monitor of serum 25OHD3 after taking calcitriol is not necessary because calcitriol inhibits the production of serum 25OHD3 by the liver (Bell et al., 1984; Luong & Nguyen, 1996). The main limitation to the clinical widespread evolution of 1,25OHD3 is its hypercalcemic side-effects.


1 - O Aguilera, C Peña, J. M García, M. J Larriba, P Ordóñez-morán, D Navarro, A Barbáchano, López de Silanes I, Ballestar E, Fraga MF, Esteller M, Gamallo C, Bonilla F, González-Sancho JM, Muñoz A. The Wnt antagonist DICKKOPF-1 gene is induced by 1alpha,25-dihydroxyvitamin D3 associated to the differentiation of human colon cancer cells. Carcinogenesis. 2007Sep;289187784
2 - S Aksu, Y Beyazit, I. C Haznedaroglu, H Canpinar, M Kekilli, A Uner, N Sayinalp, Y Büyükasik, H Goker, O. I Ozcebe, Over-expression of angiotensin-converting enzyme (CD 143) on leukemic blasts as a clue for the activated local bone marrow RAS in AML. Leuk Lymphoma. 2006May;4758916
3 - F Ambrosch, G Wiedermann, P Krepler, M Kundi, P Ambrosch, Effect of BCG vaccination of the newborn infant on the incidence and course of juvenile leukemias]. Fortschr Med. 1981Sep 17;9935138993Article in German]
4 - B Ametaj, D Beitz, T Reihardt, and B Nonnecke, 1996125dihydroxyvitamin D3 inhibits secretion of interferon-gamma by mitogen- and antigen-stimulated bovine mononuclear leukocytes. Vet Immunol Imnunopathol. 52, 77-90.
5 - E Amir, C. E Simmons, O. C Freedman, G Dranitsaris, D. E Cole, R Vieth, W. S Ooi, M Clemons, A phase 2 trial exploring the effects of high-dose (10,000 IU/day) vitamin D3 in breast cancer patients with bone metastases. Cancer. 2010Jan 15;116228491
6 - L. L An, X. T Ma, Y. H Yang, Y. M Lin, Y. H Song, K. F Wu, Marked reduction of LL-37/hCAP-18, an antimicrobial peptide, in patients with acute myeloid leukemia. Int J Hematol. 2005Jan;811457
7 - T Ando, T Ishikawa, H Kato, N Yoshida, Y Naito, S Kokura, N Yagi, T Takagi, O Handa, J Kitawaki, N Nakamura, G Hasegawa, M Fukui, E Imamoto, C Nakamura, H Oyamada, Y Isozaki, N Matsumoto, Y Nagao, M Okita, Y Nakajima, M Kurokawa, M Nukina, M Ohta, S Mizuno, M Ogata, H Obayashi, H Park, Y Kitagawa, K Nakano, T Yoshikawa, Synergistic effect of HLA class II loci and cytokine gene polymorphisms on the risk of gastric cancer in Japanese patients with Helicobacter pylori infection. Int J Cancer. 2009Dec 1;125112595602
8 - M Altas, O. F Bayrak, E Ayan, F Bolukbasi, G Silav, K. K Coskun, M Culha, F Sahin, S Sevli, I Elmaci, The effect of polymorphisms in the promoter region of the MMP-1 gene on the occurrence and invasiveness of hypophyseal adenoma. Acta Neurochir (Wien). 2010Sep;152916117
9 - S Alvarez-díaz, N Valle, G Ferrer-mayorga, L Lombardía, M Herrera, O Domínguez, M. F Segura, F Bonilla, E Hernando, A Muñoz, MicroRNA-22 is induced by vitamin D and contributes to its antiproliferative, antimigratory and gene regulatory effects in colon cancer cells. Hum Mol Genet. 2012May 15;2110215765
10 - Alves Corrêa SA, Ribeiro de Noronha SM, Nogueira-de-Souza NC, Valleta de Carvalho C, Massad Costa AM, Juvenal Linhares J, Vieira Gomes MT, Guerreiro da Silva ID. Association between the angiotensin-converting enzyme (insertion/deletion) and angiotensin II type 1 receptor (A1166C) polymorphisms and breast cancer among Brazilian women. J Renin Angiotensin Aldosterone Syst. 2009Mar;101518
11 - W Arjumand, S. T Ahmad, A Seth, A. K Saini, S Sultana, Vitamin D receptor FokI and BsmI gene polymorphism and its association with grade and stage of renal cell carcinoma in North Indian population. Tumour Biol. 2012Feb;3312331
12 - J. B Arlet, C Callens, O Hermine, L Darnige, E Macintyre, J Pouchot, L Capron, Chronic lymphocytic leukaemia responsive to vitamin D administration. Br J Haematol. 2012Jan;15611489
13 - E Arvaniti, S Ntoufa, N Papakonstantinou, T Touloumenidou, N Laoutaris, A Anagnostopoulos, K Lamnissou, F Caligaris-cappio, K Stamatopoulos, P Ghia, M Muzio, C Belessi, Toll-like receptor signaling pathway in chronic lymphocytic leukemia: distinct gene expression profiles of potential pathogenic significance in specific subsets of patients. Haematologica. 2011Nov;9611164452
14 - S Baek, Y. S Lee, H. E Shim, S Yoon, S. Y Baek, B. S Kim, S. O Oh, D Vitamin, regulates cell viability in gastric cancer and cholangiocarcinoma. Anat Cell Biol. 2011Sep;4432049
15 - K Bahar-shany, A Ravid, R Koren, Upregulation of MMP-production by TNFalpha in keratinocytes and its attenuation by vitamin D. J Cell Physiol. 201022272937
16 - B. Y Bao, H. J Ting, J. W Hsu, Y. F Lee, Protective role of 1α-dihydroxyvitamin D3 against oxidative stress in nonmalignant human prostate epithelial cells. Int J Cancer. 20081222699706
17 - D. P Bartel, 2004MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 116281297
18 - BeerTM; Lemmon, D; Lowe, BA; et al. (2003High-dose weekly oral calcitriol in patients with a rising PSA after prostatectomy or radiation for prostate carcinoma. Cancer. 9712171224
19 - BeerTM; Venner, PM; Ryan, CW; et al. (2006High dose calcitriol may reduce thrombosis in cancer patients. Br J Hematol. 135392394
20 - M. E Beildeck, M Islam, S Shah, J Welsh, S. W Byers, Control of TCF-4 expression by VDR and vitamin D in the mouse mammary gland and colorectal cancer cell lines. PLoS One. 2009Nov 17;4(11):e7872.
21 - N. H Bell, S Shaw, R. T Turner, Evidence that 1,25-dihydroxyvitamin D3 inhibits the hepatic production of 25-hydroxyvitamin D in man. J Clin Invest. 19847415401544
22 - C Bergmann, H. S Bachmann, A Bankfalvi, R Lotfi, C Pütter, C. A Wild, P. J Schuler, J Greve, T. K Hoffmann, S Lang, A Scherag, G. F Lehnerdt, Toll-like receptor 4 single-nucleotide polymorphisms Asp299Gly and Thr399Ile in head and neck squamous cell carcinomas. J Transl Med. 2011Aug 21;9:139.
23 - Y Beyazit, T Purnak, B Suvak, M Kurt, A Sayilir, T Turhan, A Tas, S Torun, T Celik, M Ibis, I. C Haznedaroglu, Increased ACE in extrahepatic cholangiocarcinoma as a clue for activated RAS in biliary neoplasms. Clin Res Hepatol Gastroenterol. 2011Oct;35106449
24 - BlankeCD; Beer, TM; Todd; et al. (2009Phase II study of calcitriol-enhanced docetaxel in patients with previously untreated metastatic or locally advanced pancreatic cancer. Investigational New Drugs. 274374378
25 - BowerM; Colston, KW; Stein, RC; et al. (1991Topical calcipotriol treatment in advanced breast cancer. Lancet. 3378743701702
26 - C. M Brosseau, G Pirianov, K. W Colston, Involvement of stress activated protein kinases (JNK and 38in 1,25 dihydroxyvitamin D3-induced breast cell death. Steroids. 2010Dec 12;75(13-14):1082-8.
27 - A. S Büchau, S Morizane, J Trowbridge, J Schauber, P Kotol, J. D Bui, R. L Gallo, The host defense peptide cathelicidin is required for NK cell-mediated suppression of tumor growth. J Immunol. 2010Jan 1;184136978
28 - G Bulut, S Fallen, E. M Beauchamp, L. E Drebing, J Sun, D. L Berry, B Kallakury, C. P Crum, J. A Toretsky, R Schlegel, A Üren, Beta-catenin accelerates human papilloma virus type-16 mediated cervical carcinogenesis in transgenic mice. PLoS One. 2011e27243.
29 - S Byers, S Shah, D Vitamin, and the regulation of Wnt/beta-catenin signaling and innate immunity in colorectal cancer. Nutr Rev. 2007Aug;65(8 Pt 2):S11820
30 - J Chang, M Kuo, H Kuo, S Hwang, J Tsai, et alalpha,25-hydroxyvitamin D3 regulates inducible nitric oxide synthase messenger RNA expression and nitric oxide release in macrophage-like RAW 264.7 cells. J Lab Clin Med. 20041431422
31 - Charalampopoulos A; Charalabopoulos, A; Batistatou, A; et al. (2010Parathormone and 1,25(OH)2D3 but not 25(OH)D3 serum levels, in an inverse correlation, reveal an association with advanced stages of colorectal cancer. Clin Exp Med. 106972
32 - A. K Chaudhary, S Pandya, R Mehrotra, M Singh, M Singh, Role of functional polymorphism of matrix metalloproteinase-2 (-1306 C/T and-168 G/T) and MMP-9 (-1562 C/T) promoter in oral submucous fibrosis and head and neck squamous cell carcinoma in an Indian population. Biomarkers. 2011Nov;16757786
33 - K. C Chiang, C. N Yeh, H. Y Chen, J. M Lee, H. H Juang, M. F Chen, M Takano, A Kittaka, T. C Chen, Nor-2α-(3-hydroxypropyl)-1α,25-dihydroxyvitamin D3 (MART-10) is a potent cell growth regulator with enhanced chemotherapeutic potency in liver cancer cells. Steroids. 2011Dec 11;761315139
34 - Y. L Cho, C Christensen, D. E Saunders, W. D Lawrence, G Deppe, V. K Malviya, J. M Malone, Combined effects of 1,25-dihydroxyvitamin D3 and platinum drugs on the growth of MCF-7 cells. Cancer Res. 1991Jun 1;5111284853
35 - H. B Choi, S. Y Roh, E. J Choi, H. Y Yoon, S. Y Kim, Y. S Hong, D. W Kim, T. G Kim, Association of HLA alleles with non-Hodgkin’s lymphoma in Korean population. Int J Hematol. 2008Mar;8722039
36 - C. M Chuang, A Monie, A Wu, C. P Mao, C. F Hung, Treatment with LL-37 peptide enhances antitumor effects induced by CpG oligodeoxynucleotides against ovarian cancer. Hum Gene Ther. 2009Apr;20430313
37 - J. W Chung, J. H Jeon, S. R Yoon, I Choi, Vitamin D upregulated protein 1 (VDUP1) is a regulator for redox signaling and stress-mediated diseases. J Dermatol. 2006Oct;33106629
38 - T. M Churilla, S. L Lesko, H. D Brereton, M Klem, P. E Donnelly, C. A Peters, Serum vitamin D levels among patients in a clinical oncology practice compared to primary care patients in the same community: a case-control study. BMJ Open. 2011Dec 19;1(2):e000397.
39 - T. M Churilla, H. D Brereton, M Klem, C. A Peters, Vitamin D Deficiency Is Widespread in Cancer Patients and Correlates With Advanced Stage Disease: A Community Oncology Experience. Nutr Cancer. 2012Mar 27. [Epub ahead of print]
40 - T Cordes, F Hoellen, C Dittmer, D Salehin, S Kümmel, M Friedrich, F Köster, S Becker, K Diedrich, M Thill, Correlation of prostaglandin metabolizing enzymes and serum PGE2 levels with vitamin D receptor and serum 25(OH)2D3 levels in breast and ovarian cancer. Anticancer Res. 2012Jan;3213517
41 - M. A Cortez, J. W Welsh, G. A Calin, Circulating MicroRNAs as Noninvasive Biomarkers in Breast Cancer. Recent Results Cancer Res. 201219515161
42 - K. D Crew, E Shane, S Cremers, D. J Mcmahon, D Irani, D. L Hershman, High prevalence of vitamin D deficiency despite supplementation in premenopausal women with breast cancer undergoing adjuvant chemotherapy. J Clin Oncol. 2009May 1;271321516
43 - Dalhoff K; Dancey, J; Astrup, L; et al. (2003A phase II study of the vitamin D analogue Seocalcitol in patients with inoperable hepatocellular carcinoma. Br J Cancer. 89252257
44 - D. D Dean, Z Schwartz, J Schmitz, O. E Muniz, Y Lu, et alVitamin D regulation of metalloproteinase activity in matrix vesicles. Connect Tissue Res. 1996353316
45 - N Denzer, T Vogt, J Reichrath, Vitamin D receptor (VDR) polymorphisms and skin cancer: A systematic review. Dermatoendocrinol. 2011Jul;3320510
46 - F Deshayes, C Nahmias, Angiotensin receptors: a new role in cancer? Trends Endocrinol Metab. 2005Sep;1672939
47 - L Dickie, L Church, L Coulthard, R Mathews, P Emery, M Mcdermott, Vitamin D downregulates intracellular toll-like receptor 9 expression and toll-like receptor 9-induced IL-6 production in human monocytes. Rheumatol. 201048146671
48 - N Ditsch, B Toth, D Mayr, M Lenhard, J Gallwas, T Weissenbacher, C Dannecker, K Friese, U Jeschke, The association between vitamin D receptor expression and prolonged overall survival in breast cancer. J Histochem Cytochem. 2012Feb;6021219
49 - P. T Donaldson, S Ho, R Williams, P. J Johnson, HLA class II alleles in Chinese patients with hepatocellular carcinoma. Liver. 2001Apr;2121438
50 - W Dong, H Li, Y Zhang, H Yang, M Guo, L Li, T Liu, Matrix metalloproteinase 2 promotes cell growth and invasion in colorectal cancer. Acta Biochim Biophys Sin (Shanghai). 2011Nov;43118408
51 - M. T Drake, M. J Maurer, B. K Link, T. M Habermann, S. M Ansell, I. N Micallef, J. L Kelly, W. R Macon, G. S Nowakowski, D. J Inwards, P. B Johnston, R. J Singh, C Allmer, S. L Slager, G. J Weiner, T. E Witzig, J. R Cerhan, Vitamin D insufficiency and prognosis in non-Hodgkin’s lymphoma. J Clin Oncol. 2010Sep 20;282741918
52 - N Du, J Feng, L. J Hu, X Sun, H. B Sun, Y Zhao, Y. P Yang, H Ren, Angiotensin II receptor type 1 blockers suppress the cell proliferation effects of angiotensin II in breast cancer cells by inhibiting AT1R signaling. Oncol Rep. 2012Jun;2761893903
53 - L Dziki, K Przybylowska, I Majsterek, R Trzcinski, M. A. A Sygut, G Polymorphism of the MMP-7 Gene Promoter Region in Colorectal Cancer. Pol Przegl Chir. 2011Nov 1;83116226
54 - O Equils, Y Naiki, A. M Shapiro, K Michelsen, D Lu, et alhydroxyvitamin D3 inhibits liposaccharide-induced immune activation in human endothelial cells. Clin Exp Immunol. 20051435864
55 - S Essa, N Denzer, U Mahlknecht, R Klein, E. M Collnot, W Tilgen, J Reichrath, VDR microRNA expression and epigenetic silencing of vitamin D signaling in melanoma cells. J Steroid Biochem Mol Biol. 2010Jul;121(1-2):110-3.
56 - S Essa, S Reichrath, U Mahlknecht, M Montenarh, T Vogt, J Reichrath, Signature of VDR miRNAs and epigenetic modulation of vitamin D signaling in melanoma cell lines. Anticancer Res. 2012Jan;3213839
57 - A Eyking, B Ey, M Rünzi, A. I Roig, H Reis, K. W Schmid, G Gerken, D. K Podolsky, E Cario, Toll-like receptor 4 variant D299G induces features of neoplastic progression in Caco-2 intestinal cells and is associated with advanced human colon cancer. Gastroenterology. 2011Dec;1416215465
58 - V Fedirko, R. M Bostick, W. D Flanders, Q Long, A Shaukat, R. E Rutherford, C. R Daniel, V Cohen, C Dash, Effects of vitamin D and calcium supplementation on markers of apoptosis in normal colon mucosa: a randomized, double-blind, placebo-controlled clinical trial. Cancer Prev Res (Phila). 2009Mar;2321323
59 - Y Feng, H Wan, J Liu, R Zhang, Q Ma, B Han, Y Xiang, J Che, H Cao, X Fei, W Qiu, The angiotensin-converting enzyme 2 in tumor growth and tumor-associated angiogenesis in non-small cell lung cancer. Oncol Rep. 2010Apr;2349418
60 - Y Feng, L Ni, H Wan, L Fan, X Fei, Q Ma, B Gao, Y Xiang, J Che, Q Li, Overexpression of ACE2 produces antitumor effects via inhibition of angiogenesis and tumor cell invasion in vivo and in vitro. Oncol Rep. 2011a Nov;265115764
61 - S Feng, J Cen, Y Huang, H Shen, L Yao, Y Wang, Z Chen, Matrix metalloproteinase-2 and-9 secreted by leukemic cells increase the permeability of blood-brain barrier by disrupting tight junction proteins. PLoS One. 2011be20599.
62 - D Ferrero, E Campa, C Dellacasa, et al2004Differentiating agents + low-dose chemotherapy in the management of old/poor prognosis patients with acute myeloid leukemia or myelodysplastic syndrome. Haematologica. 89619620
63 - T Fujioka, M Hasegawa, K Ishikura, Y Matsushita, M Sato, S Tanji, Inhibition of tumor growth and angiogenesis by vitamin D3 agents in murine renal cell carcinoma. J Urol. 199816024751
64 - N Garamszegi, S. P Garamszegi, S. P Scully, Matrix metalloproteinase-1 contribution to sarcoma cell invasion. J Cell Mol Med. 2011Jul 31. doi:j.15824934x. [Epub ahead of print]
65 - D García-plata, E Mozos, L Carrasco, R Solana, HLA molecule expression in cutaneous squamous cell carcinomas: an immunopathological study and clinical-immunohistopathological correlations. Histol Histopathol. 1993Apr;8221926
66 - E Garcion, L Sindji, G Leblondel, P Brachet, F Darcy, hydroxyvitamin D3 regulates the synthesis of γ-glutamyl transpeptidase and glutathione levels in rat primary astrocytes. J Neurochem. 19997385966
67 - GarlandCF; Grant, WB; Mohr, SB; et al. (2007What is the dose-response relationship between vitamin D and cancer risk? Nutr Rev. 658Pt.2, S91S95
68 - X Ge, X Wang, Role of Wnt canonical pathway in hematological malignancies. J Hematol Oncol. 2010Sep 15;3:33
69 - M Gilbert-sirieix, J Makoukji, S Kimura, M Talbot, B Caillou, C Massaad, L Massaad-massade, Wnt/β-catenin signaling pathway is a direct enhancer of thyroid transcription factor-1 in humanpapillary thyroid carcinoma cells. PLoS One. 2011e22280.
70 - Giovannucci E; Liu, Y; Rimm, EB; et al. (2008Prospective study of predictors of vitamin D status and cancer incidence and mortality in men. J Natl Cancer Inst. 98451459
71 - E Gocek, X Wang, X Liu, C. G Liu, G. P Studzinski, MicroRNA-32 upregulation by 1,25-dihydroxyvitamin D3 in human myeloid leukemia cells leads to Bim targeting and inhibition of AraC-induced apoptosis. Cancer Res. 2011Oct 1;711962309
72 - A. F Gombart, N Borregaard, H. P Koeffler, Human cathelicidin antimicrobial peptide (CAMP) gene is a direct target of the vitamin D receptor and is strongly up-regulated in myeloid cells by 1,25-dihydroxyvitamin D3. FASEB J. 2005Jul;199106777
73 - González-Zuloeta Ladd AM, Arias Vásquez A, Sayed-Tabatabaei FA, Coebergh JW, Hofman A, Njajou O, Stricker B, van Duijn C. Angiotensin-converting enzyme gene insertion/deletion polymorphism and breast cancer risk. Cancer Epidemiol Biomarkers Prev. 2005Sep;14921436
74 - S. C Gupta, D Hevia, S Patchva, B Park, W Koh, B. B Aggarwal, Upsides and Downsides of Reactive Oxygen Species for Cancer: The Roles of Reactive Oxygen Species in Tumorigenesis, Prevention, and Therapy. Antioxid Redox Signal. 2012Jan 16. [Epub ahead of print]
75 - G Gupta-elera, A. R Garrett, R. A Robison, O Neill, KL. The role of oxidative stress in prostate cancer. Eur J Cancer Prev. 20122115562
76 - K. K Guturi, T Mandal, A Chatterjee, M Sarkar, S Bhattacharya, U Chatterjee, M. K Ghosh, Mechanism of β-catenin mediated transcriptional regulation of EGFR expression in GSK3β inactivated prostate cancer cells. J Biol Chem. 2012Apr 5. [Epub ahead of print]
77 - T Hama, C Norizoe, H Suga, T Mimura, T Kato, H Moriyama, M Urashima, Prognostic significance of vitamin D receptor polymorphisms in head and neck squamous cell carcinoma. PLoS One. 2011e29634.
78 - H. D Halicka, H Zhao, J Li, F Traganos, G. P Studzinski, Z Darzynkiewicz, Attenuation of constitutive DNA damage signaling by 125dihydroxyvitamin D3. Aging (Albany NY). 2012Apr 11. [Epub ahead of print]
79 - W He, Y. S Kang, C Dai, Y Liu, Blockade of Wnt/β-catenin signaling by paricalcitol ameliorates proteinuria and kidney injury. J Am Soc Nephrol. 2011Jan;22190103
80 - D. M Hernández-hernández, R. M Cerda-flores, T Juárez-cedillo, J Granados-arriola, G Vargas-alarcón, T Apresa-garcía, I Alvarado-cabrero, A García-carrancá, M Salcedo-vargas, A Mohar-betancourt, Human leukocyte antigens I and II haplotypes associated with human papillomavirus 16-positive invasive cervical cancer in Mexican women. Int J Gynecol Cancer. 2009Aug;1961099106
81 - H. W Herr, V. P Laudone, R. A Badalament, H. F Oettgen, P. C Sogani, B. D Freedman, M. R Melamed, Whitmore WF Jr. Bacillus Calmette-Guérin therapy alters the progression of superficial bladder cancer. J Clin Oncol. 1988Sep;6914505
82 - Hershberger PA; Yu, WD; Modzelewski, RA; et al. (2001Calcitriol (1,25-dihydroxycholecalciferol) enhances paclitaxel antitumor activity in vitro and in vivo and accelerates paclitaxel-induced apoptosis. Clin Cancer Res. 710431051
83 - H Higiwara, H Furuhashi, K Nakaya, Y Nakamura, Effects of vitamin D3 and related compounds on angiotensin converting activity of endothelial cells and on release of plasminogen activator from them. Chem Pharm Bull. 198836485864
84 - R. L Hillyer, P Sirinvasin, M Joglekar, R. A Sikes, K. L Van Golen, A Nohe, Differential effects of vitamin D treatment on inflammatory and non-inflammatory breast cancer cell lines. Clin Exp Metastasis. 2012Dec;2989719
85 - R. A Hipskind, G Bilbe, MAP kinase signaling cascades and gene expression in osteoblasts. Front Biosci. 1998Aug 1;3:d80416
86 - M Hojjat-farsangi, M Jeddi-tehrani, A. A Amirzargar, S. M Razavi, R. A Sharifian, H Rabbani, F Shokri, Human leukocyte antigen class II allele association to disease progression in Iranian patients with chronic lymphocytic leukemia. Hum Immunol. 2008Oct;691066674
87 - C. C Hong, C. B Ambrosone, J Ahn, J. Y Choi, M. L Mccullough, V. L Stevens, et alGenetic variability in iron-related oxidative stress pathways (Nrf2, NQ01, NOS3, and HO-1), iron intake, and risk of postmenopausal breast cancer. Cancer Epidemiol Biomarkers Prev. 200716178494
88 - W Huang, L. F Yu, J Zhong, M. M Qiao, F. X Jiang, F Du, X. L Tian, Y. L Wu, Angiotensin II type 1 receptor expression in human gastric cancer and induces MMP2 and MMP9 expression in MKN-28 cells. Dig Dis Sci. 2008Jan;5311638
89 - K Ino, K Shibata, H Kajiyama, E Yamamoto, T Nagasaka, A Nawa, S Nomura, F Kikkawa, Angiotensin II type 1 receptor expression in ovarian cancer and its correlation with tumour angiogenesis and patient survival. Br J Cancer. 2006Feb 27;94455260
90 - D Iglesias-gato, S Zheng, J. N Flanagan, L Jiang, A Kittaka, T Sakaki, K Yamamoto, T Itoh, N. K Lebrasseur, G Norstedt, T. C Chen, Substitution at carbon 2 of 19nor-1α,25-dihydroxyvitamin D3 with 3-hydroxypropyl group generates an analogue with enhanced chemotherapeutic potency in PC-3 prostate cancer cells. J Steroid Biochem Mol Biol. 2011Nov;127(3-5):269-75.
91 - Y Ji, A Kutner, A Verstuyf, L Verlinden, G. P Studzinski, Derivatives of vitamins D2 and D3 activate three MAPK pathways and upregulate pRb expression in differentiating HL60 cells. Cell Cycle. 2002Nov-Dec;164105
92 - C. I Johnston, Tissue angiotensin converting enzyme in cardiac and vascular hypertrophy, repair, and remodeling. Hypertension. 19942325868
93 - A Jørgensen, Blomberg Jensen M, Nielsen JE, Juul A, Rajpert-De Meyts E. Influence of vitamin D on cisplatin sensitivity in testicular germ cell cancer-derived cell lines and in a NTera2 xenograft model. J Steroid Biochem Mol Biol. 2012Oct 23. pii: S0960-0760(12)00208-7. doi:j.jsbmb.2012.10.008. [Epub ahead of print]
94 - E Kállay, P Bareis, E Bajna, S Kriwanek, E Bonner, S Toyokuni, H. S Cross, Vitamin D receptor activity and prevention of colonic hyperproliferation and oxidative stress. Food Chem Toxicol. 2002Aug;40811916
95 - D Keizman, P Huang, M. A Eisenberger, R Pili, J. J Kim, E. S Antonarakis, H Hammers, M. A Carducci, Angiotensin system inhibitors and outcome of sunitinib treatment in patients with metastatic renal cell carcinoma: a retrospective examination. Eur J Cancer. 2011Sep;4713195561
96 - H. J Kim, J. S Bae, I. H Chang, K. D Kim, J Lee, H. D Shin, J. Y Lee, W. J Kim, W Kim, S. C Myung, Sequence variants of toll-like receptor 4 (TLR4) and the risk of prostate cancer in Korean men. World J Urol. 2012Apr;30222532
97 - J Kinoshita, S Fushida, S Harada, Y Yagi, H Fujita, S Kinami, I Ninomiya, T Fujimura, M Kayahara, M Yashiro, K Hirakawa, T Ohta, Local angiotensin II-generation in human gastric cancer: correlation with tumor progression through the activation of ERK1/2, NF-kappaB and survivin. Int J Oncol. 2009Jun;346157382
98 - E Koca, I. C Haznedaroglu, A Uner, N Sayinalp, A. E Saglam, H Goker, O. I Ozcebe, Angiotensin-converting enzyme expression of the lymphoma-associated macrophages in the lymph nodes of Hodgkin’s disease. J Natl Med Assoc. 2007Nov;99(11):1243-4, 1246-7.
99 - K. F Kölmel, J. M Grange, B Krone, G Mastrangelo, C. R Rossi, B. M Henz, C Seebacher, I. N Botev, M Niin, D Lambert, R Shafir, E. M Kokoschka, U. R Kleeberg, O Gefeller, A Pfahlberg, Prior immunisation of patients with malignant melanoma with vaccinia or BCG is associated with better survival. An European Organization for Research and Treatment of Cancer cohort study on 542 patients. Eur J Cancer. 2005Jan;41111825
100 - S Komagata, M Nakajima, S Takagi, T Mohri, T Taniya, T Yokoi, Human CYP24 catalyzing the inactivation of calcitriol is post-transcriptionally regulated by miR-125b. Mol Pharmacol. 2009Oct;7647029
101 - K Koli, J Keski-oja, Alpha, 25-dihydroxyvitamin D and its analogues down-regulate cell invasion-associated proteases in cultured malignant cells. Cell Growth Differ. 2000Apr;1142219
102 - K Köstner, N Denzer, M Koreng, S Reichrath, S Gräber, R Klein, W Tilgen, T Vogt, J Reichrath, Association of genetic variants of the vitamin D receptor (VDR) with cutaneous squamous cell carcinomas (SCC) and basal cell carcinomas (BCC): a pilot study in a German population. Anticancer Res. 2012Jan;32132733
103 - E Kulah, A Dursun, E Aktunc, S Acikgoz, M Aydin, et alEffects of angiotensin-converting enzyme gene polymorphism and serum vitamin D levels on ambulatory blood pressure measurement and left ventricular mass in Turkish hypertensive population. Blood Press Monit. 20071220713
104 - S. S Kupfer, J. R Anderson, A. E Ludvik, S Hooker, A Skol, R. A Kittles, T. O Keku, R. S Sandler, C Ruiz-ponte, S Castellvi-bel, A Castells, A Carracedo, N. A Ellis, Genetic associations in the vitamin D receptor and colorectal cancer in African Americans and Caucasians. PLoS One. 2011e26123.
105 - X Ma, C Chen, H Xiong, J Fan, Y Li, H Lin, et alNo association between SOD2 Val16Ala polymorphism and breast cancer susceptibility: a meta-analysis based on 9,710 cases and 11,041 controls. Breast Cancer Res Treat. 2010a12250914
106 - Ma Y; Yu, WD; Trump, DL; et al. (2010bEnhances antitumor activity of gemcitabine and cisplatin in human bladder cancer models. Cancer. 11632943303
107 - T Mahmoudi, M Arkani, K Karimi, A Safaei, F Rostami, E Arbabi, M. A Pourhoseingholi, S. R Mohebbi, A Nikzamir, S Romani, S Almasi, M Abbaszadeh, M Vafaei, M. R Zali, The-4817 G>A (rs2238136) variant of the vitamin D receptor gene: a probable risk factor for colorectal cancer. Mol Biol Rep. 2012May;395527782
108 - H Makni, J Daoud, Ben Salah H, Mahfoudh N, Haddar O, Karray H, Boudawara T, Ghorbel A, Khabir A, Frikha M. HLA association with nasopharyngeal carcinoma in southern Tunisia. Mol Biol Rep. 2010Jun;37525339
109 - M. A Malik, K. L Sharma, S. A Zargar, B Mittal, Association of matrix metalloproteinase-7 (-181A>G) polymorphism with risk of esophageal squamous cell carcinoma in Kashmir Valley. Saudi J Gastroenterol. 2011Sep-Oct;1753016
110 - C Mao, L. X Qiu, P Zhan, K Xue, H Ding, F. B Du, et alMnSOD Val16Ala polymorphism and prostate cancer susceptibility: a meta-analysis involving 8,962 subjects. J Cancer Res Clin Oncol. 20101369759
111 - M Marra, I. M Sordelli, A Lombardi, M Lamberti, L Tarantino, A Giudice, et alMolecular targets and oxidative stress biomarkers in hepatocellular carcinoma: an overview. J Transl Med. 2011
112 - T. F Mcguire, D. L Trump, C. S Johnson, Vitamin D induced apoptosis of murine squamous cell carcinoma cells. Selective induction of caspase-dependent MEK cleavage and up-regulation of MEKK-1. J Biol Chem. 2001Jul 13;276282636573
113 - S Michel, M Linnebacher, J Alcaniz, M Voss, R Wagner, W Dippold, C Becker, von Knebel Doeberitz M, Ferrone S, Kloor M. Lack of HLA class II antigen expression in microsatellite unstable colorectal carcinomas is caused by mutations in HLA class II regulatory genes. Int J Cancer. 2010Aug 15;127488998
114 - R Min, Z Zun, L Siyi, Y Wenjun, W Lizheng, Z Chenping, Increased expression of Toll-like receptor-9 has close relation with tumour cell proliferation in oral squamous cell carcinoma. Arch Oral Biol. 2011Sep;56987784
115 - S Minmin, X Xiaoqian, C Hao, S Baiyong, D Xiaxing, X Junjie, Z Xi, Z Jianquan, J Songyao, Single nucleotide polymorphisms of Toll-like receptor 4 decrease the risk of development of hepatocellular carcinoma. PLoS One. 2011Apr 29;6(4):e19466.
116 - K. A Moffatt, W. U Johannes, G. J Miller, α Dihydroxyvitamin D3 and platinum drugs act synergistically to inhibit the growth of prostate cancer cell lines. Clin Cancer Res. 1999Mar;53695703
117 - T Mohri, M Nakajima, S Takagi, S Komagata, T Yokoi, MicroRNA regulates human vitamin D receptor. Int J Cancer. 2009Sep 15;1256132833
118 - J Moreno, A. V Krishnan, S Swami, L Nonn, D. M Peehl, D Feldman, Regulation of prostaglandin metabolism by calcitriol attenuates growth stimulation in prostate cancer cells. Cancer Res. 2005Sep 1;6517791725
119 - Morris DL; Jourdan, JL; Finlay, I; et al. (2002Hepatic intra-arterial injection of 1,25-dihydroxyvitamin D3 in lipiodol: pilot study in patients with hepatocellular carcinoma. Int J Oncol. 21901906
120 - F Nuñez, S Bravo, F Cruzat, M Montecino, G. V De Ferrari, Wnt/β-catenin signaling enhances cyclooxygenase-2 (COX2) transcriptional activity in gastric cancer cells. PLoS One. 2011Apr 6;6(4):e18562.
121 - K Nakagawa, Y Sasaki, S Kato, N Kubodera, T Okano, Oxa-1α,25-dihydroxyvitamin D3 inhibits metastasis and angiogenesis in lung cancer. Carcinogenesis. 200526104454
122 - Y Nakai, H Isayama, H Ijichi, T Sasaki, N Sasahira, K Hirano, H Kogure, K Kawakubo, H Yagioka, Y Yashima, S Mizuno, K Yamamoto, T Arizumi, O Togawa, S Matsubara, T Tsujino, K Tateishi, M Tada, M Omata, K Koike, Inhibition of renin-angiotensin system affects prognosis of advanced pancreatic cancer receiving gemcitabine. Br J Cancer. 2010Nov 23;1031116448
123 - C Naugler, R Liwski, HLA risk markers for chronic myelogenous leukemia in Eastern Canada. Leuk Lymphoma. 2009Feb;5022549
124 - A. C Ng, S. K Kumar, S. V Rajkumar, M. T Drake, Impact of vitamin D deficiency on the clinical presentation and prognosis of patients with newly diagnosed multiple myeloma. Am J Hematol. 2009Jul;847397400
125 - H Nguyen, V. S Ivanova, L Kavandi, G. C Rodriguez, G. L Maxwell, V Syed, Progesterone and 1,25-dihydroxyvitamin D₃ inhibit endometrial cancer cell growth by upregulating semaphorin 3B and semaphorin 3F. Mol Cancer Res. 2011Nov;911147992
126 - Y Nihon-yanagi, K Terai, T Murano, T Matsumoto, S Okazumi, Tissue expression of Toll-like receptors 2 and 4 in sporadic human colorectal cancer. Cancer Immunol Immunother. 2012Jan;611717
127 - T. S Lange, A. R Stuckey, K Robison, K. K Kim, R. K Singh, C. A Raker, L Brard, T. S Lange, A. R Stuckey, K Robison, K. K Kim, R. K Singh, C. A Raker, L Brard, Effect of a vitamin D3 derivative (B3CD) with postulated anti-cancer activity in an ovarian cancer animal model. Invest New Drugs. 2010Oct;28554353
128 - M Lalor, S Floyd, P Gorak-stolinska, R Weir, R Blitz, K Branson, et al2011BCG vaccination: a role for vitamin D? PLos ONE. 6, 216709.
129 - M. J Larriba, N Valle, H. G Pálmer, P Ordóñez-morán, S Alvarez-díaz, K. F Becker, C Gamallo, A. G De Herreros, J. M González-sancho, A Muñoz, The inhibition of Wnt/beta-catenin signalling by 1alpha,25-dihydroxyvitamin D3 is abrogated by Snail1 in human colon cancer cells. Endocr Relat Cancer. 2007Mar;14114151
130 - M. J Larriba, P Ordóñez-morán, I Chicote, G Martín-fernández, I Puig, A Muñoz, H. G Pálmer, Vitamin D receptor deficiency enhances Wnt/β-catenin signaling and tumor burden in colon cancer. PLoS One. 2011e23524.
131 - G Launoy, C Milan, N. E Day, M. P Pienkowski, M Gignoux, J Faivre, Diet and squamous-cell cancer of the oesophagus: a French multicentre case-control study. Int J Cancer. 1998Mar 30;761712
132 - H. W Lee, K. B Hahm, J. S Lee, Y. S Ju, K. M Lee, K. W Lee, Association of the human leukocyte antigen class II alleles with chronic atrophic gastritis and gastric carcinoma in Koreans. J Dig Dis. 2009Nov;10426571
133 - E. S Lefkowitz, C. F Garland, Sunlight, vitamin D, and ovarian cancer mortality rates in US women. Int J Epidemiol. 1994Dec;23611336
134 - Z. Q Li, W Ding, S. J Sun, J Li, J Pan, C Zhao, W. R Wu, W. K Si, Cyr61/CCN1 Is Regulated by Wnt/β-Catenin Signaling and Plays an Important Role in the Progression of Hepatocellular Carcinoma. PLoS One. 2012e35754.
135 - E Lindhorst, P. M Schumm-draeger, J Bojunga, K. H Usadel, G Herrmann, Differences in tumor cell proliferation, HLA DR expression and lymphocytic infiltration in various types of thyroid carcinoma. Exp Clin Endocrinol Diabetes. 2002Jan;11012731
136 - L Lipworth, M Rossi, J. K Mclaughlin, E Negri, R Talamini, F Levi, S Franceschi, La Vecchia C. Dietary vitamin D and cancers of the oral cavity and esophagus. Ann Oncol. 2009Sep;209157681
137 - P. T Liu, S Stenger, H Li, L Wenzel, B. H Tan, S. R Krutzik, et alToll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science. 200631117703
138 - LiuG; Hu, X; Chakrabarty, S; et al. (2010Vitamin D mediates its action in human colon carcinoma cells in a calcium-sensing receptor-dependent manner: downregulates malignant cell behavior and the expression of thymidylate synthase and surviving and promotes cellular sensitivity to 5-FU. Int J Cancer. 126631639
139 - D Liu, W Duan, H Guo, X Xu, Y Bai, Meta-analysis of associations between polymorphisms in the promoter regions of matrix metalloproteinases and the risk of colorectal cancer. Int J Colorectal Dis. 2011Sep;2691099105
140 - D Liu, H Guo, Y Li, X Xu, K Yang, Y Bai, Association between polymorphisms in the promoter regions of matrix metalloproteinases (MMPs) and risk of cancer metastasis: a meta-analysis. PLoS One. 2012e31251.
141 - T. W Loke, D Sevfi, M Khadra, Prostate cancer incidence in Australia correlates inversely with solar radiation. BJU Int. 2011Nov;108 Suppl 26670
142 - M Lotfy, El-Kenawy Ael-M, Abdel-Aziz MM, El-Kady I, Talaat A. Elevated renin levels in patients with liver cirrhosis and hepatocellular carcinoma. Asian Pac J Cancer Prev. 201011512636
143 - S. N Louis, L Wang, L Chow, L. A Rezmann, K Imamura, MacGregor DP, Casely D, Catt KJ, Frauman AG, Louis WJ. Appearance of angiotensin II expression in non-basal epithelial cells is an early feature of malignant change in human prostate. Cancer Detect Prev. 20073153915
144 - J Lu, G Getz, E. A Miska, E Alvarez-saavedra, J Lamb, D Peck, A Sweet-cordero, B. L Ebert, R. H Mak, A. A Ferrando, J. R Downing, T Jacks, H. R Horvitz, T. R Golub, MicroRNA expression profiles classify human cancers. Nature. 2005Jun 9;43570438348
145 - LuoWJ; Chen, JY; Xu, W; et al. (2004Effects of vitamin D analogue EB1089 on proliferation and apoptosis of hepatic carcinoma cells. Zhonghua Yu Fang Yi Xue Za Zhi. 38415418article in Chinese]
146 - K. V Luong, L. T Nguyen, Coexisting hyperparathyroidism and primary hyperparathyroidism with vitamin D-deficient osteomalacia in a Vietnamese immigrant. Endocrine Practice. 19962250254
147 - K Luong, L. T Nguyen, The beneficial role of vitamin D and its analogs in cancer treatment and prevention. Crit Rev Oncol Hematol. 2010Mar;733192201
148 - Lương KVQNguyễn LTH. (2012Vitamin D and cancer. In “Advanced in Cancer Management”. InTech Publishing Co. January 2012. 116
149 - ObaraW; Mizutani, Y; Oyama, C; et al. (2008Prospective study of combined treatment with interferon-alpha and active vitamin D3 for Japanese patients with metastatic renal cell carcinoma. Int J Urol. 15794799
150 - P Ordóñez-Morán, , MJ Larriba, , HG Pálmer, , RA Valero, , A Barbáchano, , M Duñach, , AG de Herreros, , C Villalobos, , MT Berciano, , M Lafarga, , A Muñoz, . RhoA-ROCK and p38MAPK-MSK1 mediate vitamin D effects on gene expression, phenotype, and Wnt pathway in colon cancer cells. J Cell Biol. 2008 Nov 17;183(4):697-710.
151 - H Orell-kotikangas, U Schwab, P Osterlund, K Saarilahti, O Mäkitie, A. A Mäkitie, High prevalence of vitamin D insufficiency in patients with head and neck cancer at diagnosis. Head Neck. 2012Jan 27. doi:hed.21954. [Epub ahead of print]
152 - E Ozdemir, Y Kakehi, M Mishina, O Ogawa, Y Okada, D Ozdemir, O Yoshida, High-resolution HLA-DRB1 and DQB1 genotyping in Japanese patients with testicular germ cell carcinoma. Br J Cancer. 19977610134852
153 - K Ozdilli, F. S Oguz, S Anak, C Kekik, M Carin, G Gedikoglu, The frequency of HLA class I and II alleles in Turkish childhood acute leukaemia patients. J Int Med Res. 2010Sep-Oct;385183544
154 - N Panza, Del Vecchio L, Maio M, De Felice M, Lombardi G, Minozzi M, Zappacosta S. ong association between an HLA-DR antigen and thyroid carcinoma. Tissue Antigens. 1982Aug;2021558
155 - H. G Pálmer, J. M González-sancho, J Espada, M. T Berciano, I Puig, J Baulida, M Quintanilla, A Cano, A. G De Herreros, M Lafarga, A Muñoz, D Vitamin, promotes the differentiation of colon carcinoma cells by the induction of E-cadherin and the inhibition of beta-catenin signaling. J Cell Biol. 2001Jul 23;154236987
156 - Palmieri-SevierA; Palmieri, GM; Baumgartner, CJ; Britt, LG. (1993Case report: long-term remission of parathyroid cancer: possible relation to vitamin D and calcitriol therapy. Am J Med Sci. 3065309312
157 - A Pardanani, M. T Drake, C Finke, T. L Lasho, S. A Rozell, T Jimma, A Tefferi, Vitamin D insufficiency in myeloproliferative neoplasms and myelodysplastic syndromes: clinical correlates and prognostic studies. Am J Hematol. 2011Dec;861210136
158 - M. R Park, J. H Lee, M. S Park, J. E Hwang, H. J Shim, S. H Cho, I. J Chung, W. K Bae, Suppressive effect of 19-nor-1α-25-dihydroxyvitamin D2 on gastric cancer cells and peritoneal metastasis model. J Korean Med Sci. 2012Sep;279103743
159 - S. L Parsons, S. A Watson, H. M Collins, N. R Griffin, P. A Clarke, R. J Steele, Gelatinase (MMP-2 and-9) expression in gastrointestinal malignancy. Br J Cancer. 1998Dec;78111495502
160 - R Partyka, M Gonciarz, P Jalowiecki, D Kokocinska, T Byrczek, VEGF and metalloproteinase 2 (MMP 2) expression in gastric cancer tissue. Med Sci Monit. 2012Apr 1;18(4):BR130134
161 - N Pendás-franco, J. M García, C Peña, N Valle, H. G Pálmer, M Heinäniemi, C Carlberg, B Jiménez, F Bonilla, A Muñoz, J. M González-sancho, DICKKOPF-4 is induced by TCF/beta-catenin and upregulated in human colon cancer, promotes tumour cell invasion and angiogenesis and is repressed by 1alpha,25-dihydroxyvitamin D3. Oncogene. 2008a Jul 24;2732446777
162 - N Pendás-franco, O Aguilera, F Pereira, J. M González-sancho, A Muñoz, D Vitamin, and Wnt/beta-catenin pathway in colon cancer: role and regulation of DICKKOPF genes. Anticancer Res. 2008Sep-Oct;28(5A):261323
163 - X Peng, A Vaishnav, G Murillo, F Alimirah, K. E Torres, R. G Mehta, Protection against cellular stress by 25-hydroxyvitamin D3 in breast epithelial cells. J Cell Biochem. 2010Aug 15;1106132433
164 - W. J Peng, J. Q Zhang, B. X Wang, H. F Pan, M. M Lu, J Wang, W. J Peng, J. Q Zhang, B. X Wang, H. F Pan, M. M Lu, J Wang, Prognostic value of matrix metalloproteinase 9 expression in patients with non-small cell lung cancer. Clin Chim Acta. 2012Jul 11;413(13-14):1121-6.
165 - L. J Peppone, A. S Rickles, M. C Janelsins, M. R Insalaco, K. A Skinner, L. J Peppone, A. S Rickles, M. C Janelsins, M. R Insalaco, K. A Skinner, The Association Between Breast Cancer Prognostic Indicators and Serum 25OH Vitamin D Levels. Ann Surg Oncol. 2012Mar 24. [Epub ahead of print]
166 - J. L Pérez-castrillón, I Justo, A Sanz, D De Luis, A Dueñas, Effect of angiotensin converting enzyme inhibitors on 1,25(OH)2 D levels of hypertensive patients. Relationship with ACE polymorphisms. Horm Metab Res. 2006388126
167 - P Polakis, 2000Wnt signaling and cancer. Genes Dev 1418371851
168 - T Punzi, A Fabris, G Morucci, P Biagioni, M Gulisano, M Ruggiero, Pacini S. C-reactive protein levels and vitamin d receptor polymorphisms as markers in predicting cachectic syndrome in cancer patients. Mol Diagn Ther. 2012Apr 1;16211524
169 - J Qiu, S Shao, G Yang, Z Shen, Y Zhang, Association of Toll like receptor 9 expression with lymph node metastasis in human breast cancer. Neoplasma. 20115832515
170 - S. H Raffegerst, G Hoelzlwimmer, S Kunder, J Mysliwietz, L Quintanilla-martinez, D. J Schendel, Diverse hematological malignancies including hodgkin-like lymphomas develop in chimeric MHC class II transgenic mice. PLoS One. 2009Dec 31;4(12):e8539.
171 - RainaV; Cunninham, D; Gilchrist, N; Soukop, M. (1991Alphacalcidol is a nontoxic, effective treatment of follicular small-cleaved cell lymphoma. Br J Cancer. 63463465
172 - R Ray, M Banks, H Abuzahra, V. J Eddy, K. S Persons, M. S Lucia, J. R Lambert, M. F Holick, Effect of dietary vitamin D and calcium on the growth of androgen-insensitive human prostate tumor in a murine model. Anticancer Res. 2012Mar;32372731
173 - A Ravid, D Rocker, A Machlenkin, C Rotem, A Hochman, G Kessler-icekson, U. A Liberman, R Koren, Dihydroxyvitamin D3 enhances the susceptibility of breast cancer cells to doxorubicin-induced oxidative damage. Cancer Res. 1999Feb 15;5948627
174 - C Ren, M. Z Qiu, D. S Wang, H. Y Luo, D. S Zhang, Z. Q Wang, F. H Wang, Y. H Li, Z. W Zhou, R. H Xu, Prognostic effects of 25hydroxyvitamin D levels in gastric cancer. J Transl Med. 2012Jan 27;10:16.
175 - Repin IuMBCG vaccine immunotherapy after radical operations for lung cancer]. Vestn Khir Im I I Grek. 1992Jul-Aug;149(7-8):11-6. [Article in Russian]
176 - S. G Rhodes, L. A Terry, J Hope, R. G Hewinson, H. M Vordermeier, dihydroxyvitamin D3 and development of tuberculosis in cattle. Clin Diagn Lab Immunol. 2003Nov;106112935
177 - A Ristimäki, N Honkanen, H Jänkälä, P Sipponen, M Härkönen, Expression of cyclooxygenase-2 in human gastric carcinoma. Cancer Res. 1997Apr 1;577127680
178 - B Rivas-santiago, R Hernandez-pando, C Carranza, E Juarez, J. L Contreras, et alExpression of cathelicidin LL-37 during Mycobacterium tuberculosis infection in human alveolar macrophages, monocytes, neutrophils, and epithelial cells. Infect Immunity. 20087693541
179 - T. E Robsahm, S Tretli, A Dahlback, J Moan, D Vitamin, from sunlight may improve the prognosis of breast-, colon- and prostate cancer (Norway). Cancer Causes Control. 2004Mar;15214958
180 - K Rockett, R Brookes, I Udalova, V Vidal, A Hill, and D Kwiatkowski, 1998125hydroxyvitamin D3 induces nitric oxide synthase and suppresses growth of Mycobacterium tuberculosis in a human macrophage-like cell line. Infect Immun. 66, 5314-5321.
181 - A Rogalska, A Gajek, M Szwed, Z Józwiak, A Marczak, The role of reactive oxygen species in WP 631-induced death of human ovarian cancer cells: a comparison with the effect of doxorubicin. Toxicol In Vitro. 201125171220
182 - D. E Rollison, A. L Cole, K. H Tung, M. L Slattery, K. B Baumgartner, T Byers, R. K Wolff, A. R Giuliano, Vitamin D intake, vitamin D receptor polymorphisms, and breast cancer risk among women living in the southwestern U.S. Breast Cancer Res Treat. 2012Apr;132268391
183 - C. L Roth, C. T Elfers, D. P Figlewicz, S. J Melhorn, G. J Morton, et alVitamin D deficiency in obese rats exacerbates NAFLD and increases hepatic resistin and toll-like receptor activation. Hepatol. 2011Oct 12. [Epub ahead of print].
184 - E Ruza, E Sotillo, L Sierrasesúmaga, C Azcona, A Patiño-garcía, Analysis of polymorphisms of the vitamin D receptor, estrogen receptor, and collagen Ialpha1 genes and their relationship with height in children with bone cancer. J Pediatr Hematol Oncol. 2003Oct;25107806
185 - K Sadeghi, B Wessner, U Laggner, M Ploder, D Tamandl, et alVitamin D3 down-regulates monocyte TLR expression and triggers hyporesponsiveness to pathogen-associated molecular patterns. Eur J Immunol. 20063636170
186 - J Sandholm, J. H Kauppila, C Pressey, J Tuomela, A Jukkola-vuorinen, M Vaarala, M. R Johnson, K. W Harris, K. S Selander, Estrogen receptor-α and sex steroid hormones regulate Toll-like receptor-9 expression and invasive function in human breast cancer cells. Breast Cancer Res Treat. 2012Apr;13224119
187 - D Salehin, C Haugk, M Thill, T Cordes, M William, B Hemmerlein, M Friedrich, Serum 25-hydroxyvitamin D levels in patients with vulvar cancer. Anticancer Res. 2012Jan;32126570
188 - W Saliba, O Barnett, H. S Rennert, I Lavi, G Rennert, The relationship between serum 25(OH)D and parathyroid hormone levels. Am J Med. 2011124116570
189 - S Sardar, A Chakraborty, M Chatterjee, Comparative effectiveness of vitamin D3 and dietary vitamin E on peroxidation of lipids and enzymes of the hepatic antioxidant system in Sprague-Dawley rats. Int J Vitam Nutr Res. 1996663945
190 - J Schauber, K Iffland, S Frisch, T Kudlich, B Schmausser, M Eck, T Menzel, A Gostner, H Lührs, W Scheppach, Histone-deacetylase inhibitors induce the cathelicidin LL-37 in gastrointestinal cells. Mol Immunol. 2004Jul;41984754
191 - J Scherberich, M Kellermeyer, C Ried, A Hartinger, alpha-calcidol modulates major human monocyte antigens and toll-like receptors TRL2 and TRL4 in vitro. Eur J Med Res. 20051017982
192 - B Schöttker, D Ball, C Gellert, H Brenner, Serum 25hydroxyvitamin D levels and overall mortality. A systematic review and meta-analysis of prospective cohort studies. Ageing Res Rev. 2012Feb 17. [Epub ahead of print]
193 - G. G Schwartz, M. H Wang, M Zang, R. K Singh, G. P Siegal, alpha,25-Dihydroxyvitamin D (calcitriol) inhibits the invasiveness of human prostate cancer cells. Cancer Epidemiol Biomarkers Prev. 1997Sep;6972732
194 - T. D Shanafelt, M. T Drake, M. J Maurer, C Allmer, K. G Rabe, S. L Slager, G. J Weiner, T. G Call, B. K Link, C. S Zent, N. E Kay, C. A Hanson, T. E Witzig, J. R Cerhan, Vitamin D insufficiency and prognosis in chronic lymphocytic leukemia. Blood. 2011Feb 3;117514928
195 - I. M Shui, L. A Mucci, P Kraft, R. M Tamimi, S Lindstrom, K. L Penney, K Nimptsch, B. W Hollis, N Dupre, E. A Platz, M. J Stampfer, E Giovannucci, Vitamin D-Related Genetic Variation, Plasma Vitamin D, and Risk of Lethal Prostate Cancer: A Prospective Nested Case-Control Study. J Natl Cancer Inst. 2012May 2;1049690699
196 - J Sikora, M Frydrychowicz, M Kaczmarek, B Brzezicha, I Mozer-lisewska, M Szczepanski, J Zeromski, TLR receptors in laryngeal carcinoma- immunophenotypic, molecular and functional studies. Folia Histochem Cytobiol. 2010Dec;48462431
197 - H. G Skinner, and G. G Schwartz, 2009The relation of serum parathyroid hormone and serum calcium to serum levels of Prostatic-specific antigen: a population-based study. Cancer Epidemiol Biomarkers Prev. 181128692873
198 - C. A Slapek, J. F Desforges, T Fogaren, et al1992Treatment of acute myeloid leukemia in the elderly with low-dose cytarabine, hydroxyurea, and calcitriol. Am J Hematol. 41178183
199 - M. L Slattery, R. K Wolff, K Curtin, F Fitzpatrick, J Herrick, J. D Potter, B. J Caan, W. S Samowitz, Colon tumor mutations and epigenetic changes associated with genetic polymorphism: insight into disease pathways. Mutat Res. 2009Jan 15;660(1-2):12-21.
200 - M. L Slattery, J. S Herrick, K. L Bondurant, R. K Wolff, Toll-like receptor genes and their association with colon and rectal cancer development and prognosis. Int J Cancer. 2012Jun 15;13012297480
201 - D Somjen, S Katzburg, M Grafi-cohen, E Knoll, O Sharon, G. H Posner, Vitamin D metabolites and analogs induce lipoxygenase mRNA expression and as well as reactive oxygen species (ROS) production in human bone cell line. J Steroid Biochem Mol Biol. 2011123859
202 - E. J Song, M. J Kang, Y. S Kim, S. M Kim, S. E Lee, C. H Kim, D. J Kim, J. H Park, Flagellin promotes the proliferation of gastric cancer cells via the Toll-like receptor 5. Int J Mol Med. 2011Jul;2811159
203 - P Srivastava, T. A Lone, R Kapoor, R. D Mittal, Association of Promoter Polymorphisms in MMP 2 and TIMP2 with Prostate Cancer Susceptibility in North India. Arch Med Res. 2012Feb 25. [Epub ahead of print]
204 - W. F Stenson, S. L Teitelbaum, Z Bar-shavit, Arachidonic acid metabolism by a vitamin D3-differentiated human leukemic cell line. J Bone Miner Res. 1988Oct;3556171
205 - M Stio, M Martinesi, A Simoni, U Zuegel, A Steinmeyer, R Santi, C Treves, G Nesi, The novel vitamin D analog ZK191784 inhibits prostate cancer cell invasion. Anticancer Res. 2011Dec;311240918
206 - I Sundar, J Hwang, S Wu, J Sun, I Rahman, Deletion of vitamin D receptor leads to premature emphysema/COPD by increased matrix metalloproteinase and lymphoid aggregates formation. Biochem Biophys Res Commun. 201140612733
207 - S Swami, A. V Krishnan, J. Y Wang, K Jensen, R Horst, M. A Albertelli, D Feldman, Dietary Vitamin D3 and 125Dihydroxyvitamin D3 (Calcitriol) Exhibit Equivalent Anticancer Activity in Mouse Xenograft Models of Breast and Prostate Cancer. Endocrinology. 2012Mar 27. [Epub ahead of print]
208 - J Svedlund, M Aurén, M Sundström, H Dralle, G Akerström, P Björklund, G Westin, Aberrant WNT/β-catenin signaling in parathyroid carcinoma. Mol Cancer. 2010Nov 15;9:294.
209 - H Takala, J. H Kauppila, Y Soini, K. S Selander, K. S Vuopala, P. P Lehenkari, J Saarnio, T. J Karttunen, Toll-like receptor 9 is a novel biomarker for esophageal squamous cell dysplasia and squamous cell carcinoma progression. J Innate Immun. 2011366318
210 - K Tamaki, A Saitoh, Y Kubota, hydroxyvitamin D3 decreases the interferon-gamma (IFN-gamma) induced HLA-DR expression but not intercellular adhesion molecule 1 (ICAM-1) on human keratinocytes. Reg Immunol. 199032237
211 - J Tangrea, K Helzlsouer, P Pietinen, P Taylor, B Hollis, J Virtamo, D Albanes, Serum levels of vitamin D metabolites and the subsequent risk of colon and rectal cancer in Finnish men. Cancer Causes Control. 1997Jul;8461525
212 - Y. T Tee, Y. F Liu, J. T Chang, S. F Yang, S. C Chen, C. P Han, P. H Wang, C. L Liao, Single-Nucleotide Polymorphisms and Haplotypes of Membrane Type 1 Matrix Metalloproteinase in Susceptibility and Clinical Significance of Squamous Cell Neoplasia of Uterine Cervix in Taiwan Women. Reprod Sci. 2012Apr 23. [Epub ahead of print]
213 - M Thill, F Hoellen, S Becker, C Dittmer, D Fischer, et alExpression of prostaglandin- and vitamin D-metabolising enzymes in benign and malignant breast cells. Anticancer Res. 20123236772
214 - P. M Timms, N Mannan, G. A Hitman, K Noonan, P. G Mills, et alCirculating MMP9, vitamin D and variation in the TIMP-1 response with VDR genotype: mechanisms for inflammatory damage in chronic disorders? Q J Med. 20029578796
215 - Ting HJ; Hsu, J; Bao,BY; Lee, YF. (2007Docetaxel-induced growth inhibition an apoptosis in androgen indepenpent prostate cancer cells are enhanced by 1alpha,25-dihydroxyvitamin D3. Cancer Lett. 247122129
216 - E. J Tokar, M. M Webber, Cholecalciferol (vitamin D3) inhibits growth and invasion by up-regulating nuclear receptors and 25-hydroxylase (CYP27A1) in human prostate cancer cells. Clin Exp Metastasis. 200522327584
217 - N Tokuda, N Mizuki, M Kasahara, R. B Levy, hydroxyvitamin D3 down-regulation of HLA-DR on human peripheral blood monocytes. Immunol. 19927534954
218 - N Tokuda, R Levy, hydroxyvitamin D3 stimulates phagocytosis but suppresses HLA-DR and CD13 antigen expression in human mononuclear phagocytes. Proc Soc Exp Biol Med. 199621124450
219 - T Tone, H Eto, K Katsuoka, K Nishioka, S Nishiyama, Suppression of gamma-interferon induced HLA-DR antigen expression on normal and transformed keratinocytes by 1,25 (OH)2 vitamin D3. Nippon Hifuka Gakkai Zasshi. 199110151925Article in Japanese].
220 - T Tone, H Eto, T Katou, F Otani, S Nishiyama, Alpha,25-dihydroxyvitamin D modulation of HLA-DR mRNA induced by gamma-interferon in cultured epithelial tumor cell lines. J Dermatol. 1993205814
221 - A Turna, A Pekçolaklar, M Metin, I Yaylim, A Gurses, The effect of season of operation on the survival of patients with resected non-small cell lung cancer. Interact Cardiovasc Thorac Surg. 2012Feb;1421515
222 - K Ueno, H Hirata, S Majid, Y Chen, M. S Zaman, Z. L Tabatabai, Y Hinoda, R Dahiya, Wnt antagonist DICKKOPF-3 (Dkk-3) induces apoptosis in human renal cell carcinoma. Mol Carcinog. 2011Jun;50644957
223 - X Wang, E Gocek, C. G Liu, G. P Studzinski, MicroRNAs181 regulate the expression of 27Kip1in human myeloid leukemia cells induced to differentiate by 1,25-dihydroxyvitamin D3. Cell Cycle. 2009a Mar 1;8(5):736-41.
224 - S Wang, F Wang, X Shi, J Dai, Y Peng, X Guo, et alAssociation between manganese superoxide dismutase (MnSOD) Val-9Ala polymorphism and cancer risk- A meta-analysis. Eur J Cancer. 2009b45287481
225 - H. C Wang, S Choudhary, Reactive oxygen species-mediated therapeutic control of bladder cancer. Nat Rev Urol. 2011860816
226 - W. L Wang, N Chatterjee, S. V Chittur, J Welsh, M. P Tenniswood, Effects of 1α,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011a May 18;10:58.
227 - S Wang, X Wang, J Wu, Y Lin, H Chen, X Zheng, C Zhou, L Xie, Association of vitamin D receptor gene polymorphism and calcium urolithiasis in the Chinese Han population. Urol Res. 2011b Nov 25. [Epub ahead of print]
228 - Y. Y Wang, L. Z Wang, L. R Sun, Antitumor effect of BCG on growth of transplanted human myeloid leukemia HL-60 cells in nude mice]. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2011c Jun;1937259
229 - J. Y Wang, S Swami, A. V Krishnan, D Feldman, Combination of calcitriol and dietary soy exhibits enhanced anticancer activity and increased hypercalcemic toxicity in a mouse xenograft model of prostate cancer. Prostate. 2012a Mar 27. doi:pros.22516. [Epub ahead of print]
230 - H Wang, G Tan, L Dong, L Cheng, K Li, Z Wang, H Luo, Circulating MiR-125b as a Marker Predicting Chemoresistance in Breast Cancer. PLoS One. 2012be34210.
231 - G. E Weitsman, A Ravid, U. A Liberman, R Koren, The role of 38MAP kinase in the synergistic cytotoxic action of calcitriol and TNF-alpha in human breast cancer cells. J Steroid Biochem Mol Biol. 2004May;89-90(1-5):361-4.
232 - J Welsh, L. N Zinser, L Mianecki-morton, J Martin, S. E Waltz, H James, G. M Zinser, Age-related changes in the epithelial and stromal compartments of the mammary gland in normocalcemic mice lacking the vitamin D3 receptor. PLoS One. 2011Jan 26;6(1):e16479
233 - B. D White, A. J Chien, D. W Dawson, Dysregulation of Wnt/β-catenin signaling in gastrointestinal cancers. Gastroenterology. 2012Feb;142221932
234 - E Wieczorek, E Reszka, J Gromadzinska, W Wasowicz, Genetic polymorphism of matrix metalloproteinases in breast cancer. Neoplasma. 201259323747
235 - S Wilop, S Von Hobe, M Crysandt, A Esser, R Osieka, E Jost, Impact of angiotensin I converting enzyme inhibitors and angiotensin II type 1 receptor blockers on survival in patients with advanced non-small-cell lung cancer undergoing first-line platinum-based chemotherapy. J Cancer Res Clin Oncol. 2009Oct;13510142935
236 - B. M Wolpin, K Ng, Y Bao, P Kraft, M. J Stampfer, D. S Michaud, J Ma, J. E Buring, H. D Sesso, I. M Lee, N Rifai, B. B Cochrane, J Wactawski-wende, R. T Chlebowski, W. C Willett, J. E Manson, E. L Giovannucci, C. S Fuchs, Plasma 25-hydroxyvitamin D and risk of pancreatic cancer. Cancer Epidemiol Biomarkers Prev. 2012Jan;2118291
237 - T. C Woo, R Choo, M Jamieson, S Chander, R Vieth, Pilot study: potential role of vitamin D (Cholecalciferol) in patients with PSA relapse after definitive therapy. Nutr Cancer. 2005511326
238 - K Woodson, J. A Tangrea, T. A Lehman, R Modali, K. M Taylor, K Snyder, et alManganese superoxide dismutase (MnSOD) polymorphism, alpha-tocopherol supplementation and prostate cancer risk in the alpha-tocopherol, beta-carotene cancer prevention study (Finland). Cancer Causes Control. 2003145138
239 - W. K Wu, J. J Sung, K. F To, L Yu, H. T Li, Z. J Li, K. M Chu, J Yu, C. H Cho, The host defense peptide LL-37 activates the tumor-suppressing bone morphogenetic protein signaling via inhibition of proteasome in gastric cancer cells. J Cell Physiol. 2010Apr;223117886
240 - K Wu, D Feskanich, C. S Fuchs, A. T Chan, W. C Willett, B. W Hollis, M. N Pollak, E Giovannucci, Interactions between plasma levels of 25hydroxyvitamin D, insulin-like growth factor (IGF)-1 and C-peptide with risk of colorectal cancer. PLoS One. 2011ae28520.
241 - Y Wu, T Miyamoto, K Li, H Nakagomi, N Sawada, S Kira, H Kobayashi, H Zakohji, T Tsuchida, M Fukazawa, I Araki, M Takeda, Decreased expression of the epithelial Ca2+ channel TRPV5 and TRPV6 in human renal cell carcinoma associated with vitamin D receptor. J Urol. 2011bDec;1866241925
242 - T Yamaji, M Iwasaki, S Sasazuki, H Sakamoto, T Yoshida, S Tsugane, Association between plasma 25-hydroxyvitamin D and colorectal adenoma according to dietary calcium intake and vitamin D receptor polymorphism. Am J Epidemiol. 2012Feb 1;175323644
243 - W Yan, W Zhang, L Sun, Y Liu, G You, Y Wang, C Kang, Y You, T Jiang, Identification of MMP-9 specific microRNA expression profile as potential targets of anti-invasion therapy in glioblastoma multiforme. Brain Res. 2011Sep 9;141110815
244 - Y. H Yang, G. G Zheng, G Li, B Zhang, Y. H Song, K. F Wu, Expression of LL-37/hCAP-18 gene in human leukemia cells. Leuk Res. 2003Oct;271094750
245 - S Yim, P Dhawan, C Ragunath, S Christakos, G Diamond, Induction of cathelicidin in normal and CF bronchial epithelial cells by 1,25-dihydroxyvitamin D3. J Cys Fibros. 20076403410
246 - L Yin, N Grandi, E Raum, U Haug, V Arndt, H Brenner, Meta-analysis: longitudinal studies of serum vitamin D and colorectal cancer risk. Aliment Pharmacol Ther. 2009Jul 1;30211325
247 - S Yoshioka, M. L King, S Ran, H Okuda, MacLean JA 2nd, McAsey ME, Sugino N, Brard L, Watabe K, Hayashi K. WNT7A regulates tumor growth and progression in ovarian cancer through the WNT/β-catenin pathway. Mol Cancer Res. 2012Mar;10346982
248 - H Yu, S. S Xu, Q. Q Cheng, L. M He, Z Li, Expression and clinical significance of Toll-like receptors in human renal carcinoma cell 786-0 and normal renal cell HK-2]. Zhonghua Yi Xue Za Zhi. 2011Jan 11;91212931Article in Chinese]
249 - W Yuan, W Pan, J Kong, W Zheng, F Szeto, et aldihydroxyvitamin D3 suppresses renin gene transcription by blocking the activity of the cyclic AMP response element in the renin gene promoter. J Biol Chem. 20072822982130
250 - J. M Yuk, D. M Shin, K. S Song, K Lim, K. H Kim, S. H Lee, J. M Kim, J. S Lee, T. H Paik, J. S Kim, E. K Jo, Bacillus calmette-guerin cell wall cytoskeleton enhances colon cancer radiosensitivity through autophagy. Autophagy. 2010Jan;614660
251 - Z Xia, W Liu, S Li, G Jia, Y Zhang, C Li, Z Ma, J Tian, J Gong, Expression of matrix metalloproteinase-9, type IV collagen and vascular endothelial growth factor in adamantinous craniopharyngioma. Neurochem Res. 2011Dec;3612234651
252 - W Xiang, J Kong, S Chen, L Cao, G Qiao, et alCardiac hypertrophy in vitamin D receptor knockout mice: role of the systemic and cardiac renin-angiotensin systems. Am J Phys Endocrinol Met. 2005E12532
253 - H Xu, A Soruri, R. K Gieseler, J. H Peters, dihydroxyvitamin D3 exerts opposing effects to IL-4 on MHC class-II antigen expression, accessory activity, and phagocytosis of human monocytes. Scand J Immunol. 19933853560
254 - X Zhao, X Wang, W Wu, Z Gao, J Wu, D. H Garfield, H Wang, J Wang, J Qian, H Li, L Jin, Q Li, B Han, D Lu, C Bai, Matrix metalloproteinase-2 polymorphisms and clinical outcome of Chinese patients with nonsmall cell lung cancer treated with first-line, platinum-based chemotherapy. Cancer. 2011Nov 9. doi:cncr.26669. [Epub ahead of print]
255 - L. Y Zhang, K. W Ren, Meta-analysis of MMP2-1306T allele as a protective factor in digestive cancer. Arch Med Res. 2011Apr;42323943
256 - W Zhang, H. C Yang, Q Wang, Z. J Yang, H Chen, S. M Wang, Z. M Pan, B. J Tang, Q. Q Li, L Li, Clinical value of combined detection of serum matrix metalloproteinase-9, heparanase, and cathepsin for determining ovarian cancer invasion and metastasis. Anticancer Res. 2011a Oct;311034238
257 - J Zhang, J. S Harrison, G. P Studzinski, Isoforms of 38MAPKgamma and delta contribute to differentiation of human AML cells induced by 1,25-dihydroxyvitamin D₃. Exp Cell Res. 2011b Jan 1;317(1):117-30.
258 - Q Zhang, Y Ma, Y. F Cheng, W. J Li, Z Zhang, S. Y Chen, Involvement of reactive oxygen species in 2-methoxyestradiol-induced apoptosis in human neuroblastoma cells. Cancer Lett. 2011c31320110
259 - L. F Zhang, Y. Y Mi, Q Cao, W Wang, C Qin, J. F Wei, Y. J Zhou, Y. F Li, M Tang, W. M Liu, W Zhang, J. G Zou, Update analysis of studies on the MMP-9-1562 C>T polymorphism and cancer risk. Mol Biol Rep. 2012a Apr;394343541
260 - J Zhang, H Zhang, X Zhang, Z Yu, Synergistic effect of retinoic acid and vitamin D analog EB1089induced apoptosis of hepatocellular cancer cells. Cytotechnology. 2012b Oct 16. [Epub ahead of print]
261 - W Zhou, R. S Heist, G Liu, K Asomaning, D. S Neuberg, B. W Hollis, J. C Wain, T. J Lynch, E Giovannucci, L Su, D. C Christiani, Circulating 25-hydroxyvitamin D levels predict survival in early-stage non-small-cell lung cancer patients. J Clin Oncol. 2007Feb 10;25547985
262 - L Zhou, R Zhang, W Yao, J Wang, A Qian, M Qiao, Y Zhang, Y Yuan, Decreased expression of angiotensin-converting enzyme 2 in pancreatic ductal adenocarcinoma is associated with tumor progression. Tohoku J Exp Med. 2009Feb;217212331
263 - L Zhou, R Zhang, L Zhang, W Yao, J Li, Y Yuan, Angiotensin-converting enzyme 2 acts as a potential molecular target for pancreatic cancer therapy. Cancer Lett. 2011Aug 1;30711825
264 - Zhuo de X, Niu XH, Chen YC, Xin DQ, Guo YL, Mao ZB. Vitamin D3 up-regulated protein 1(VDUP1) is regulated by FOXO3A and miR-17-5p at the transcriptional and post-transcriptional levels, respectively, in senescent fibroblasts. J Biol Chem. 2010Oct 8;2854131491501
265 - E. I Zimmerman, C. M Dollins, M Crawford, S Grant, S. P Nana-sinkam, K. L Richards, S. M Hammond, L. M Graves, Lyn kinase-dependent regulation of miR181 and myeloid cell leukemia-1 expression: implications for drug resistance in myelogenous leukemia. Mol Pharmacol. 2010Nov;7858117
266 - R Van Der Knaap, C Siemes, J. W Coebergh, C. M Van Duijn, A Hofman, B. H Stricker, Renin-angiotensin system inhibitors, angiotensin I-converting enzyme gene insertion/deletion polymorphism, and cancer: the Rotterdam Study. Cancer. 2008Feb 15;112474857
267 - M Varsavsky, R Reyes-garcía, M Cortés-berdonces, A García-martin, P Rozas-moreno, M Muñoz-torres, Serum 25 OH vitamin D concentrations and calcium intake are low in patients with prostate cancer. Endocrinol Nutr. 2011Nov;58948791
268 - Vink-van Wijngaarden T, Pols HA, Buurman CJ, van den Bemd GJ, Dorssers LC, Birkenhäger JC, van Leeuwen JP. Inhibition of breast cancer cell growth by combined treatment with vitamin D3 analogues and tamoxifen. Cancer Res. 1994Nov 1;542157117
269 - M Villumsen, S Sørup, T Jess, H Ravn, T Relander, J. L Baker, C. S Benn, T. I Sørensen, P Aaby, A Roth, Risk of lymphoma and leukaemia after bacille Calmette-Guérin and smallpox vaccination: a Danish case-cohort study. Vaccine. 2009Nov 16;274969508
270 - M Volante, I Rapa, M Gandhi, G Bussolati, D Giachino, M Papotti, Y. E Nikiforov, RAS mutations are the predominant molecular alteration in poorly differentiated thyroid carcinomas and bear prognostic impact. J Clin Endocrinol Metab. 2009Dec;9412473541