Open Access is an initiative that aims to make scientific research freely available to all. To date our community has made over 100 million downloads. It’s based on principles of collaboration, unobstructed discovery, and, most importantly, scientific progression. As PhD students, we found it difficult to access the research we needed, so we decided to create a new Open Access publisher that levels the playing field for scientists across the world. How? By making research easy to access, and puts the academic needs of the researchers before the business interests of publishers.
We are a community of more than 103,000 authors and editors from 3,291 institutions spanning 160 countries, including Nobel Prize winners and some of the world’s most-cited researchers. Publishing on IntechOpen allows authors to earn citations and find new collaborators, meaning more people see your work not only from your own field of study, but from other related fields too.
To purchase hard copies of this book, please contact the representative in India:
CBS Publishers & Distributors Pvt. Ltd.
www.cbspd.com
|
customercare@cbspd.com
Hepatocarcinoma is one of the most common lethal human malignant tumors, mainly because of active angiogenesis. This kind of high angiogenesis often accounts for early metastasis, rapid recurrence, and poor survival. Growing evidence has proved that hepatocarcinoma angiogenesis is closely associated with multiple risk factors, such as DNA damages resulting from hepatitis B and C virus infection, aflatoxin B1 exposure, ethanol intake, and obesity. Genetic alterations and genomic instability, probably resulting from low DNA damage repair response (DRR) and the following unrepaired DNA lesions, are also increasingly recognized as important risk factors of hepatocarcinoma angiogenesis. Dysregulation of DRRs and signaling to cell cycle checkpoints involving in DRR pathways may accelerate the accumulation of DNA damages and trigger the dysregulation of angiogenesis-related genes and the progression of hepatocarcinoma. In this review, we discussed DNA damages/DRRs and angiogenesis during hepatocarcinogenesis and their interactive regulations. Hopefully, the review will also remind the medical researchers and clinic doctors of further understanding and validating the values of DNA damages/DRRs in hepatocarcinoma angiogenesis.
Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, China
Department of Pathology, The Affiliated Hospital of Youjiang Medical University for Nationalities, China
Guangxi Clinic Research Center of Hepatobiliary Diseases, China
Zhou-Ximao Long
Zhoupu Middle School, East China Normal University, China
Xiao-Ying Huang
Department of Pathology, The Affiliated Hospital of Youjiang Medical University for Nationalities, China
Jin-Guang Yao
Department of Pathology, The Affiliated Hospital of Youjiang Medical University for Nationalities, China
Qiang Xia
Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, China
Yan Deng
Department of Epidemiology, Youjiang Medical University for Nationalities, China
*Address all correspondence to: sjtulongxd@263.net
1. Introduction
Hepatocellular carcinoma, also termed as hepatocarcinoma, is one of the most common malignant tumors, with more than 500,000 new cases per year [1]. Until recently, it has been frequent to consider hepatocarcinoma as a tumor with low incidence in the western world but with high incidence in the eastern countries [1]. However, increasing data exhibit that the incidence of this tumor has increased in both western and eastern countries. Etiologically, several risk factors, including hepatitis B virus (HBV), hepatitis C virus (HCV), aflatoxin B1 (AFB1), and alcohol, have been identified for increasing disease incidence worldwide [2]. Although molecular mechanisms of hepatocarcinoma caused by these risk factors have not still been clear, chronic and permanent liver damage and damage response may play a vital role. Macrocosmically, liver damage consists of a series of pathological changes, such as chronic hepatitis, liver cirrhosis, nodular hyperplasia, and dysplasia [3]. Microcosmically, chronic DNA damage, including the formation of DNA adducts, DNA strand break and bulk, gene mutations, and genomic instability, is the most important type [4].
Because of early blood metastasis and high death rate of this malignancy, it has become the third most common cause of cancer-associated deaths worldwide. This death risk could be explained by high angiogenesis capacities of hepatocarcinoma [1, 2]. Increasing evidence has exhibited that hepatocarcinoma patients with high microvessel density (MVD) in tumor tissues would feature a poor prognosis, and angiogenesis has been regarded as an important marker predicting the risk of invasiveness and metastasis [5]. This chapter summarizes the latest findings in hepatocarcinoma angiogenesis, DNA damage, and damage repair response (DRR). We also try to shed light on the effects of DNA damage and dysregulation of DRR on tumor angiogenesis.
Several previous reviews have summarized the angiogenesis in hepatocarcinoma [5, 6, 7]. In brief, angiogenesis is a kind of crucial biological function and survival potential for normal organism development, growth, and adaptation to new environment. The dynamic balance between increasing and decreasing potential of angiogenesis is essential in the different physiological and pathological conditions, such as injury cure, damage repair, inflammatory procession, tumor progression, blindness, and ischemia. Hepatocarcinoma angiogenesis was extensively studied via cell models, experimental animal models, and human tumor samples [5, 6, 7]. Accumulating data have proved that local hypoxia in tumor tissues and the change in genome resulting from genetic or environmental risk factors will lead to the secretion and synthetics of angiogenetic regulative factors and triggering angiogenesis [8, 9, 10]. In hepatocarcinoma tissues, the process of angiogenesis consists of the following several stages: sprouting, extracellular matrix component (ECMs) reconstruction, endothelial cell (EC) migration and proliferation, lumen formation, and stabilization of newborn vessels (Figure 1) [11].
Figure 1.
Angiogenesis procession in hepatocarcinoma. The procession of angiogenesis consists of: (1) sprouting and budding; (2) ECM remodeling; (3) EC proliferation and migration; (4) lumen formation and three-D organization; and (5) stabilization of nascent vessels.
The establishment of conditions allowing ECs proliferation and migration, which often results from local hypoxia, first facilitates endothelial sprouting and budding. During this stage, hypoxia induces the secretion and synthetics of angiogenetic factors, such as nitric oxide (NO), vascular endothelial growth factor (VEGF), CD31, angiopoietin-1, and so on [11]. The NO-induced vasodilation and VEGF-caused high permeability result in the extravasation of plasma components (including fibrinogen and fibrin). Together with ECMs, these plasma components lay down and form provisional scaffolds for migrating ECs. The basement membranes and ECMs (mainly consisting of collagen I and IV and laminin) are next degraded, and subsequently, ECs migrate into local sites and proliferate. Increasing proliferation of ECs in the local hypoxia tissues leads to the formation of nascent vessels with lumen. After that, nascent vessels are recruited and structurally stabilized under the conditions of physical forces and a series of molecules such as platelet-derived growth factor β (PDFG-β), angiopoietin-1, angiopoietin-2, VEGF, and transforming growth factor β1 (TGF-β1) [7, 11, 12].
Vessels in hepatocarcinoma differ from other liver diseases or normal vessels [5, 11, 13]. First, tumor vessels typically appear as irregular diameter and abnormal branching patterns [5]. Second, pericytes of vessels are often incompletely covered or lost; furthermore, their basement membranes are also incomplete [11]. Third, tumor vessels sometimes form irregular channels and the walls of these channels are comprised of cancer cells. Moreover, the endothelial cells may be replaced by cancer cells partially or completely. Finally, angiogenesis in hepatocarcinoma not only appears abnormal architecture but also accompanies abnormal molecular expression and regulation [6, 14]. These characteristics result in abnormal structures and function for hepatocarcinoma; however, they can provide some important cues for early diagnosis and therapeutic strategies for cases with hepatocarcinoma.
2.2. Angiogenesis regulation in hepatocarcinoma
A series of angiogenic and antiangiogenic factors (Tables 1 and 2) regulate the angiogenesis process in hepatocarcinoma [5]. During the process of hepatocarcinoma angiogenesis, hypoxia and VEGF family play a vital role. Hypoxia in local tumor tissues, an important pathophysiological phenomenon caused by rapid growth of tumor, leads to the expression of hypoxia-inducible factor (HIF)-1α, which is a key inducible factor for angiogenesis in hypoxia tissues [7, 14]. On the one hand, HIF-1α can induce the expression of hypoxia-response-related genes like NO, VEGF, transforming growth factor (TGF) α and β, adrenomedullin (ADM), LDL-receptor-related protein 1 (LRP1), and leptin; on the other hand, local hypoxia status in tumor tissues also downregulates the expression of antiangiogenic factors such as thrombospondin-1 (TS1) and -2 (TS2) [15, 16, 17]. Additionally, growing literature has shown that lots of factors, including genetic or acquired alterations in the oncogenes (i.e., Ras, c-Jun, and Myc) and tumor suppressor genes (i.e., TP53), Hepatitis B Virus X (HBx) protein, chromobox 4, and DNA damage induced by chronic inflammation and AFB1 exposure, can increase the expression proangiogenic factors [18, 19, 20, 21, 22, 23]. For example, HBx protein has a potential for increasing HIF-1α expression via promoting transcriptional and translational activity and therefore accelerating angiogenesis during carcinogenesis process of hepatocarcinoma [24]. Recent studies have reported that chromobox 4 (a known transcriptional regulator and also a SUMO E3 enzyme) can promote angiogenesis via stabilizing HIF-1 in hepatocarcinoma [18, 19]. VEGF (including its glycoprotein family members VEGF-A, -B, -C, and -D) is another important angiogenic factor that always upregulates in most cases with hepatocarcinoma [5]. The upregulation of VEGF in hepatocarcinoma is proved not only to increase tumor neovascularization but also to accelerate tumor growth via in vitro cell experiments and animal models. The role of VEGF is mediated mainly by two receptors: VEGF-R1 (also called Flt-1) and VEGF-R2 (also termed as KDR/Flk-1). Both VEGF-R1 and VEGF-R2 have tyrosine kinase activity and are normally expressed in hepatic parenchyma cells including endothelial cells of portal and sinusoidal tracts [5, 6]. In hepatocarcinoma, both mRNA and protein amount of them are increasing noticeably in the tumor tissues compared to peri-tumor tissues [25]. Some other factors, such as angiopoietin 1 and 2, involve in the regulation of angiogenesis in hepatocarcinoma (Tables 1 and 2) [5, 6, 13]. Together, increasing angiogenic potential but decreasing antiangiogenic potential facilitates hepatocarcinoma angiogenesis.
In the past decades, several biomarkers, such as VEGF, angiogenin, and MVD, have been selected for elucidating angiogenic potential of hepatocarcinoma. Table 3 summarized the potential of these biomarkers for hepatocarcinoma angiogenesis and angiogenesis-related tumor biological actions. Among these biomarkers, VEGF is concerned especially because of its clinic significance. For example, a hospital-based clinic samples analyses (including 7 cases with liver low-grade dysplastic nodule [DN], 8 cases with liver high-grade DN, 11 cases with early hepatocarcinoma, 17 cases with small hepatocarcinoma, and 21 cases with advanced hepatocarcinoma) by Park et al. [26] showed that the amount of VEGF increased gradually from low-grade DN to early hepatocarcinoma. Furthermore, this increasing expression of VEGF is significantly associated with neoangiogenesis (marked by MVD with CD34 staining) and cancer cell proliferation. Collectively, we can conclude that increasing VEGF expression and MVD are positively associated with tumor vascularization and the following tumor progression and poor survival of tumor cases. Furthermore, increasing evidence has exhibited that serum levels of VEGF are not only parallel with the amount in tumor tissues but also can predict therapy response of patients with hepatocarcinoma [29, 30, 31, 32]. Thus, VEGF may be useful for improving therapeutic strategies of hepatocarcinoma based on the angiogenesis thesis.
(1) VEGF expression increases gradually from LGD to eHCC. (2) The sHCCs has an increasing neoangiogenesis and cell proliferation compared to aHCCs. (3) The levels of VEGF expression are positively associated with MVD (marked by CD34 staining).
(1) TEMs are involved in HCC angiogenesis. (2) The frequency of circulating TEMs was significantly higher in HCC than non-HCC patients. (3) The TEMs have higher diagnostic value for HCC than AFP, PIVKA-II and ANG-2.
3.1. DNA damage induced by risk factors for hepatocarcinoma
Multiple risk factors, including HBV and HCV infection, AFB1 exposure, ethanol consumption, and obesity, have been reported to correlate with hepatocarcinogenesis (Figure 2) [4]. These risk factors can induce multiple types of DNA damage, such as DNA single-stand break (SSB), double-strand break (DSB), base damage, DNA-adduct formation, oxidation damage, gene mutation, chromosomal aberration, and genomic instability [4]. Results from epidemiological and experimental studies show that viral-DNA damage relationship is characterized by: (1) the integration of viral gene (such as HBx gene) into the genome of liver cells and resulting genomic instability of host cells [21, 24, 40, 41]; (2) TP53 mutation conducted by HBx integration resulting in abnormal cell response, including DNA repair, cell proliferation and cycle, and apoptosis potential [22]; (3) HCV core interfering the formation of Mre11/Rad50/Nbs1 (MRN) complex through the bind with Nbs1 [5]; (4) the inhibition of such DNA repair proteins as Ataxia telangiectasia mutated kinase (ATM) [42, 43]; and (5) inducing dysregulation of signal pathways, including Wnt/β-catenin pathway, sex steroid pathway, p38MAPK pathway, PI3K/Akt pathway, transforming growth factor 𝛽 (TGF𝛽) pathway, NF-𝜅B pathway, and so on [11].
Figure 2.
Risk factors-induced DNA damage and damage repair response during hepatocarcinoma. Abbreviations: HBV, hepatitis B virus; HCV, hepatitis C virus; AFB1, aflatoxin B1; AFBO, AFB1-8,9-epoxide; IL, interleukin; TGF, transforming growth factor.
For AFB1-induced DNA damage, adducts formation and gene mutations are concerned especially [44]. AFB1 is a known I-type chemical hepatocarcinogen produced mainly by A. parasiticus and A. flavus and a suspected risk factor for hepatocarcinoma in some dependent areas such as Sub-Saharan area, the southeast region of Asia, and the coast of southeast China. Results from prospective epidemiological and animal studies have exhibited that AFB1-induced DNA damage plays a vital role in the process of hepatocarcinoma caused by AFB1 exposure [40, 45]. Studies of AFB1 metabolism have further proved that cytochrome P450 (CYP) enzymes in hepatocytes can facilitate AFB1 into its epoxy compound, also termed as AFB1-8,9-epoxide (AFBe). AFBe can covalently bind to genomic DNA and ultimately induce multiple types of DNA damage [46, 47]. Increasing evidence exhibits that AFB1 can multiplicatively interact with HBV and/or HCV infection during hepatocarcinogenesis, and that, this multiplicative interaction may be associated with more noticeable DNA damage induced by both AFB1 exposure and HBV/HCV infection [23]. Epidemiological studies based on the case-control design with a large sample have proved that patients with chronic virus hepatitis (including B and C type) will feature increasing hepatocarcinoma risk under the conditions of high AFB1 exposure [46]. Furthermore, patients with high AFB1 often companies with chronic virus infection and faces higher frequency of gene mutation like TP53 and ras [47]. Interestingly, the mutation at the codon 249 of TP53 gene, namely G:C > T:A mutation resulting in the change of arginine to serine, has been identified as a relatively specifically change and named AFB1-induced hot-spot mutation [44]. This mutation may lead to the dysfunction of TP53 protein and abnormal cell actions like promoting cell growth, inhibiting cell apoptosis, and inhibiting transcription mediated by TP53 [40].
Other risk factors like alcohol intake also cause malignant transformation of hepatocytes. Chronic ethanol intake will significantly increase hepatocarcinoma risk (about five times) if more than 80 g/day × 10 years. Actually, less than this amount of uptake also increases cancer risk in spite of nonsignificance [48]. Although mechanisms are not still clear, increasing data have shown that chronic hepatic injury, abnormal regeneration, and cirrhosis may act some role in hepatocarcinogenesis [4]. Pathological and molecular biological studies display that acetaldehyde, an important metabolic product of ethanol, can bind to DNA and form DNA adducts. The DNA adduct formation caused could trigger replication errors and/or mutations in tumor suppressor genes and/or oncogene [4]. Additionally, oxidative DNA damage is more noticeable in tissues with hepatocarcinoma than peri-tumor tissues [40, 46]. However, it is unclear whether acetaldehyde-DNA adducts and oxidative damages are true carcinogens and how they trigger hepatocarcinogenesis [4, 49]. Therefore, future studies on DNA damage are needed to better validate these risk factors and detailed molecular mechanisms.
3.2. DRR in hepatocarcinoma
DNA damage will trigger DRR pathways, a kind of prompt signal event which can harmonize whether cells obtain cycle arrest for DNA repair or induce death for eliminating cells with severe DNA damage and genomic instability [4]. In human, cells develop several types of surveillance mechanisms consisting of SSB repair (SSBR), DSB repair (DSBR), base excision repair (BER), base mismatch repair (MMR), and nucleotide excision repair (NER) (Figure 2) [4, 40]. Among these DNA repair pathways, BER, MMR, and NER can repair base damage such as base mismatches, AFB1-DNA adducts, DNA pyrimidine dimers, and DNA damage induced by irradiation and anticancer drugs. SSBR can repair SSB that is a severe DNA damage, if not repaired quickly, will disrupt genic transcription and replication and ultimately results in lethal DNA damage [40]. DSBR pathway involves in homologous recombination (HR), single-strand annealing (SSA), and nonhomologous end joining (NHEJ). HR pathway can repair DSBs through an accurate repair method using the undamaged homologous chromosome or sister-chromatid as DNA repair temple; whereas NHEJ and SSA pathways are nonhomologous repair methods and usually lead to essential mutagenesis, so far as to induce chromosomal aberrations, abnormal cell cycle, and/or uncontrolled cell proliferation [50]. During DRR pathways, DNA repair genes play a central role [4]. Dysregulation of DRR caused by DNA repair genic mutations or low DNA repair capacity will increase hepatocarcinoma risk. Table 4 summarized the effects of abnormal DRR in hepatocarcinogenesis. This evidence shows that dysregulation of DRR resulting from mutations in DNA repair genes and corresponding dysfunctions may promote hepatocarcinogenesis through the following pathways: (1) increasing individuals’ susceptibility to risk factors such as hepatitis virus infection and AFB1 exposure [40, 60, 101]; (2) increasing individuals’ susceptibility to cancer [45]; (3) increasing amount of carcinogens-DNA adducts in liver tissues [40]; (4) increasing amount of adducts (such as AFB1-DNA and AFB1-albumin adducts) in the peripheral WBCs and affecting immune reaction [61]; (5) increasing the frequency of tumor suppressor genes or oncogenes like Ras and TP53M [40, 47, 52, 61, 79]; and (6) interacting with risk factors during hepatocarcinogenesis [23]. Thus, the potential of DRR pathways should play an important function for hepatocarcinogenesis.
Arg to His at codon 280 Arg to Gln at codon 399 Arg to Trp at codon 194
(1) Increasing individuals’ susceptibility to HBV infection (2) Increasing individuals’ susceptibility to hepatocarcinoma (3) Increasing amount of AFB1-DNA adducts in liver tissues (4) Increasing amount of adducts (including AFB1-DNA and AFB1-albumin adducts) in the peripheral WBCs (5) Increasing the frequency of TP53M (6) Increasing MVD
(1) Increasing individuals’ susceptibility to hepatocarcinoma (2) Increasing amount of AFB1-DNA adducts in liver tissues (3) Increasing amount of adducts (including AFB1-DNA and AFB1-albumin adducts) in the peripheral WBCs (4) Increasing the frequency of TP53M (5) Associating with hepatocarcinoma clinicopathological features (6) Increasing MVD
(1) Increasing individuals’ susceptibility to hepatocarcinoma (2) Increasing amount of AFB1-DNA adducts in liver tissues (3) Increasing amount of adducts (including AFB1-DNA and AFB1-albumin adducts) in the peripheral WBCs (4) Increasing the frequency of TP53M (5) Associating with hepatocarcinoma clinicopathological features (6) Increasing MVD
(1) Increasing individuals’ susceptibility to HBV infection (2) Increasing individuals’ susceptibility to hepatocarcinoma (3) Associating with biological actions of hepatocarcinoma cells, such as increasing XRCC5 expression inhibiting cancer cells proliferation (4) Functioning as a tumor suppressor by inducing S-phase arrest in a TP53-dependent pathway
(1) Increasing individuals’ susceptibility to hepatocarcinoma (2) Decreasing Toll-like receptor 4 (TLR4) against hepatocarcinogenesis (3) Increasing DNA damage, and promoting programmed cell death in TLR4-deficient livers (4) Early diagnostic value for hepatocarcinoma
(1) Increasing individuals’ susceptibility to AFB1 exposure (2) Increasing individuals’ susceptibility to hepatocarcinoma (3) Increasing amount of AFB1-DNA adducts in liver tissues (4) Increasing amount of adducts (including AFB1-DNA and AFB1-albumin adducts) in the peripheral WBCs (5) Increasing the frequency of TP53M (6) Interacting with AFB1 exposure during hepatocarcinogenesis (7) Increasing MVD
(1) Increasing individuals’ susceptibility to hepatocarcinoma (2) Increasing amount of AFB1-DNA adducts in liver tissues (3) Increasing amount of adducts (including AFB1-DNA and AFB1-albumin adducts) in the peripheral WBCs (4) Increasing the frequency of TP53M and decreasing DRR potential (5) Associating with hepatocarcinoma clinicopathological features (6) Increasing XPC expression (7) Increasing MVD
(1) Increasing individuals’ susceptibility to hepatocarcinoma (2) Increasing amount of AFB1-DNA adducts in liver tissues (3) Increasing amount of adducts (including AFB1-DNA and AFB1-albumin adducts) in the peripheral WBCs (4) Increasing the frequency of TP53M and decreasing DRR potential (5) Interacting with gender during hepatocarcinoma (6) Increasing MVD
(1) Increasing hepatocarcinoma risk (2) The amount of ERCC1 expression in tissues with hepatocarcinoma decreases cancer cells’ sensitivity on anti-cancer drugs (3) Predicting the outcome of hepatocarcinoma patients receiving TACE treatment
Ser to Ala at codon 1981 Ser to Ala at codon 1893 Ser to Ala at codon 367 Ser to Ala at codon 2996 Autophosphorylation at codon 1981 Ser
(1) The functional deficiency in radioresistant DNA synthesis and substrate phosphorylation such as TP53, Chk2, Nbs1, and SMCI (2) Increasing cells’ sensitivity to risk factors and risk factors-induced DNA damage such as adduct formation and chromosome aberrations (3)The functional dysregulation for G2/M checkpoint (4) Extending activations of DNA damage signaling pathways to reach S phase arrest in hepatocarcinoma cells (5) Leading to ATM unable to be released from other ATM molecules, and increasing gene mutation risk
Risk factors induced DNA damages and dysregulated DRRs are regarded as molecular events [4]. In human, risk factors for hepatocarcinoma can manifest acute and chronic DNA damage. Acute and noticeable DNA damages often lead to severe chromosome aberration and even cell death, whereas chronic DNA damages are the earliest molecular change in hepatocytes and ultimately result in hepatocarcinoma [40]. In the past decades, angiogenesis induced by dysregulation of DRR pathways may act as a vital role in the process of hepatocarcinoma. Evidence from epidemiological and clinicopathological studies has shown that higher potential of angiogenesis is in the liver of patients with chronic DNA damage and low DRR capacity [40, 102, 103, 104, 105]. For example, Pastukh et al. [102] investigated the association between recruitment of DNA repair enzymes involving in BER pathway and VEGF expression via a chromatin immunoprecipitation technique. They found that hypoxia-induced reactive oxygen species (ROS) stress caused promoter base modifications targeted to hypoxic response elements (HREs) and increased VEGF expression. During this modification, 8-oxoguanine (8-oxodG, an oxidative DNA damage product) in VEGF promoter was temporally correlated with binding of human 8-oxodG glycosylase 1 (hOGG1, a BER repair enzyme), HIF-1α, redox effector factor-1, endonuclease one, and breaks in DNA strands. If 8-oxodG was decreased in the promoter region of VEGF, VEGF expression would downregulate [102]. Recent molecular epidemiological studies have further proved that genetic variants in hOGG1 genes increase hepatocarcinoma risk and modify the prognosis of this malignancy [103, 104, 105]. Collectively, these data suggest that increasing ROS like 8-oxodG resulting from low DRR capacity may promote angiogenesis.
Studies from high HBV and HCV infection and high AFB1 exposure area also display that the degrees of DNA damages are positively associated with MVD in tumor tissues from hepatocarcinoma [20, 55, 75, 79, 82]. For example, Lu et al. [20] investigated the effects of XRCC4 expression in tumor tissues on clinicopathological features and prognosis of hepatocarcinoma and found that decreasing XRCC4 expression was related to low DRR capacity, causing the formation of DNA adducts and TP53M. The dysregulation of XRCC4 may promote tumor proliferation and increase MVD. Several other studies further show that the low DRR capacity resulting from significant mutations in coding region of DNA repair genes (such as XRCC4, XRCC1, XPC, XPD, and XRCC7) increases MVD (Table 4) [21, 40, 52, 55, 59, 61, 62, 79, 80, 82]. Results from Lu et al. [20] and our studies [61, 62] showed that genetic alterations in the coding regions of XRCC4 gene (including Ala to Ser at codon 247 and Thr to Ala at codon 56) can decrease levels of XRCC4 protein expression and cause increasing amount of AFB1-DNA adducts and mutative frequency of TP53 gene in tissues with hepatocarcinoma. They also found that the amount of AFB1-induced DNA adducts, including 8,9-dihydro-8-(N7-guanyl)-9-hydroxy-AFB1 (AFB1-N7-Gua) and formamidopyridine AFB1 adduct (AFB1-FAPy), was positively associated with the number of microvessels (a biomarker for angiogenesis). Results from our studies [79, 106, 107] furthermore displayed that three low DNA repair markers related to AFB1, including tumor risk, TP53M frequency, and AFB1-FAPy adduct amount, were significantly correlated with the number of microvessels in liver tissues. These individuals with high AFB1-FAPy adduct level in liver tissues had an increasing risk of high MVD than those low adduct level (OR = 1.68, 95% CI = 1.45–2.87) [106]. Liu et al. [108] and Wang et al. [109] further proved that the upregulation of microRNA-429 and microRNA-24 expression in tissues with hepatocarcinoma not only increased the amount of AFB1-DNA adducts and the number of microvessels but also grew tumor metastasis risk via vessels and shorted patients’ survival. Recent evidence has shown that microRNA-24/microRNA-429 can modify the capacity of DDR via controlling Nbs1 (a regulator of DRR) [110, 111] and angiogenesis via regulating the crosstalk between the pro-contractile transforming growth factor-β/bone morphogenetic protein (TGF-β/BMP) signal (inducing a quiescent ‘contractile’ phenotype) and the pro-synthetic platelet-derived growth factor (PDGF) signal (causing a proliferative ‘synthetic’ phenotype) [112, 113]. This suggests that microRNA-24/microRNA-429 may play an important regulative role between DRR capacity and angiogenesis. Taken together, this evidence proves that low DRR-induced MVD augmentation is regulated by the amount of DNA damage.
Evidence from in vitro and in vivo studies further shows that dysregulation of DRRs and signaling to cell cycle checkpoints (CCCs) may modify hepatocarcinoma angiogenesis. CCCs involving in DRRs mainly encompass G1/S and G2/M checkpoint [114]. During G1/S checkpoint, both ATR and ATM act as central activators for DRR via inducing the phosphorylation of p53 protein which can activate p21 (a Cdk inhibitor). ATM/TP53/P21 pathway also plays an important function controlling G2/M procession [114]. The dysregulation of these factors and signal pathways can change the status of angiogenesis [115, 116, 117, 118, 119]. For example, Qin et al. [115] found that E2F1, an important cell cycle regulator, can modify angiogenesis via controlling VEGF expression by p53-dependent way. In this control model, deficient phenotype of E2F1 will result in VEGF overexpression, while its positive phenotype decreases VEGF expression [115]. Factors controlling cell shape and cytosol can regulate the cycle of vessel endothelial cells and angiogenesis [116, 117]. In mice model with the deficiency of BCL-2 (an important regulatory factor in DDRs), cells featured increasing DNA damage [118]; the inhibition of BCL-2 will result in the arrest of cells in S phrase and suppression of tumor angiogenesis [119]. In an integrated genomic study (including 5 hepatocarcinoma patients with hepatitis D visus [HDV] and 7 HDV-positive cirrhosis cases), Diaz et al. [120] investigated the association between HDV-related hepatocarcinoma and potential signal pathways involved in DNA damage and repair and cell cycle and found significant interactions of DDR/cell cycle-related genes, such as BRCA1, BARD1, CDK1, CDKN2C, CCNA2, CCNB1, CCNE2, GSK3B, H2AFX, MSH2, NPM1, PRKDC, and TOP2A. Results from the t-SNP (t-distributed stochastic neighbor embedding analyses) further exhibited that HUS1, BRCA1, BARD1, GADD45, DNA-damage-induced 14-3-3σ, and MSH2 gene involving in DRRs valuably scored with regulatory genes (such as ATM, TP53, NO, and epidermal growth factor), which involve in G2/M checkpoint and angiogenesis [120]. The dysregulation of HUS1 and corresponding genotoxin-activated checkpoint complex (also termed as Rad9-Rad1-Hus1complex) will cause abnormal DRR capacity and cell cycle in response to DNA damage and promote the alteration of hematogenous metastatic phenotype for hepatocarcinoma [121, 122]. The genetic alterations and abnormal expression of BRCA1 and GADD45 (two important regulatory factors in DRR and apoptosis pathways) in hepatocytes can also change TP53-dependent CCCs and VEGF expression [123, 124]. Altogether, these studies have proved that the dysregulation of DDRs can cause the abnormal regulation of CCCs and change the status of hepatocarcinoma angiogenesis.
Detailed molecular mechanisms of DRR dysregulation promoting hepatocarcinoma angiogenesis have still not been fully understood. Several possible pathways may play some important roles. First, DNA damage agents induce NO synthase and increase the expression of VEGF and HGF [125, 126]. Second, DNA damage agents like AFB1 cause the mutations of such genes as TP53, ras, and DNA repair genes. Activation of oncogenes and inactivation of tumor suppression genes and DNA repair genes lead to uncontrolled expression of genes involving in angiogenesis such as VEGF and Ang-1/2 [5, 6]. Third, genetic alterations in DRR pathways may alter the microenvironment of tumor and promote angiogenesis [127, 128, 129]. Fourth, the abnormal DRRs may accelerate the accumulation of DNA damages and trigger the dysregulation of angiogenesis-related genes and the progression of hepatocarcinoma. Finally, some metabolic products (such as AFBO) or nucleotide sequences (HBx) of DNA agents can bind to genomic DNA of hepatocytes and may increase the activation of VEGF HREs [22, 40, 41, 45]. Taken together, under the conditions of low DRR capacity and/or chronic risk factors, DNA damages will accumulate in hepatocytes and ultimately induce hepatocarcinogenesis and tumor angiogenesis.
Abnormal angiogenesis and DNA damages/DRRs are two important pathophysiological events in the process of hepatocarcinogenesis. Recently, it has become a growing evidence of DNA damage and repair and angiogenesis in hepatocarcinogenesis. Low DRR capacity resulting genetic or obtained alterations may lead to the accumulation of DNA damages and induce angiogenesis and ultimately promote hepatocarcinoma development. The main challenge for this field is the explanations of molecular basis and regulative signal pathways of DNA damages/DRRs interacting with angiogenesis during hepatocarcinogenesis. A better understanding of hypervascular feature and corresponding mechanisms of hepatocarcinoma on the basis of DNA damage/DRR pathway may be helpful for the medical researchers and clinic doctors exploring and validating hepatocarcinogenesis but also for them designing safe and efficient antiangiogenic drugs.
The authors declare no competing financial interests. This study was supported in part by the National Natural Science Foundation of China (Nos. 81860489, 81760502, 81572353, 81372639, 81472243, 81660495, and 81460423), the Innovation Program of Guangxi Municipal Education Department (Nos. 201204LX674 and 201204LX324), Innovation Program of Guangxi Health Department (No. Z2013781), the Natural Science Foundation of Guangxi (Nos. 2017GXNSFAA198002, 2017GXNSFGA198002, 2016GXNSFDA380003, 2015GXNSFAA139223, 2013GXNSFAA019251, 2014GXNSFDA118021, and 2014GXNSFAA118144), Research Program of Guangxi “Zhouyue Scholar” (No. 2017-38), Research Program of Guangxi Specially-invited Expert (No. 2017-6th), the “12th Five” Planning Program of Guangxi Education Science (No. 2015C397), the Innovative Program of Guangxi Graduate Education (No. JGY2015139), Research Program of Guangxi Clinic Research Center of Hepatobiliary Diseases (No.AD17129025), and Open Research Program from Molecular Immunity Study Room Involving in Acute & Severe Diseases in Guangxi Colleges and Universities (Nos. kfkt20160062 and kfkt20160063).
1.Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA: A Cancer Journal for Clinicians. 2015;65:87-108. DOI: 10.3322/caac.21262
2.Blum HE, Spangenberg HC. Hepatocellular carcinoma: An update. Archives of Iranian Medicine. 2007;10:361-371. DOI: 07103/AIM.0015
3.Aravalli RN, Cressman EN, Steer CJ. Cellular and molecular mechanisms of hepatocellular carcinoma: An update. Archives of Toxicology. 2013;87:227-247. DOI: 10.1007/s00204-012-0931-2
4.Yang SF, Chang CW, Wei RJ, Shiue YL, Wang SN, Yeh YT. Involvement of DNA damage response pathways in hepatocellular carcinoma. BioMed Research International. 2014;2014:153867. DOI: 10.1155/2014/153867
5.Semela D, Dufour JF. Angiogenesis and hepatocellular carcinoma. Journal of Hepatology. 2004;41:864-880. DOI: 10.1016/j.jhep.2004.09.006
6.Sun HC, Tang ZY. Angiogenesis in hepatocellular carcinoma: The retrospectives and perspectives. Journal of Cancer Research and Clinical Oncology. 2004;130:307-319. DOI: 10.1007/s00432-003-0530-y
7.Sugimachi K, Tanaka S, Terashi T, Taguchi K, Rikimaru T, Sugimachi K. The mechanisms of angiogenesis in hepatocellular carcinoma: Angiogenic switch during tumor progression. Surgery. 2002;131:S135-S141. DOI: 10.1067/msy.2002.119365
8.Machado MV, Janeiro A, Miltenberger-Miltenyi G, Cortez-Pinto H. Genetic polymorphisms of proangiogenic factors seem to favor hepatocellular carcinoma development in alcoholic cirrhosis. European Journal of Gastroenterology & Hepatology. 2014;26:438-443. DOI: 10.1097/MEG.0000000000000044
9.He Y, Ni J, Chen S, Jiang Y, Jia S, Gao Y. The vascular endothelial growth factor-2549 insertion/deletion polymorphism is not associated with susceptibility to hepatocellular carcinoma in Chinese. DNA and Cell Biology. 2010;29:393-396. DOI: 10.1089/dna.2009.1015
10.Kong SY, Park JW, Lee JA, Park JE, Park KW, Hong EK, et al. Association between vascular endothelial growth factor gene polymorphisms and survival in hepatocellular carcinoma patients. Hepatology. 2007;46:446-455. DOI: 10.1002/hep.21720
11.Chaparro M, Sanz-Cameno P, Trapero-Marugan M, Garcia-Buey L, Moreno-Otero R. Mechanisms of angiogenesis in chronic inflammatory liver disease. Annals of Hepatology. 2007;6:208-213. DOI: PMID18007549
12.Wietecha MS, Cerny WL, DiPietro LA. Mechanisms of vessel regression: Toward an understanding of the resolution of angiogenesis. Current Topics in Microbiology and Immunology. 2013;367:3-32. DOI: 10.1007/82_2012_287
13.Medina J, Arroyo AG, Sanchez-Madrid F, Moreno-Otero R. Angiogenesis in chronic inflammatory liver disease. Hepatology. 2004;39:1185-1195. DOI: 10.1002/hep.20193
14.Kim KR, Moon HE, Kim KW. Hypoxia-induced angiogenesis in human hepatocellular carcinoma. Journal of Molecular Medicine (Berlin, Germany). 2002;80:703-714. DOI: 10.1007/s00109-002-0380-0
15.Chiu DK, Tse AP, Xu IM, Di Cui J, Lai RK, Li LL, et al. Hypoxia inducible factor HIF-1 promotes myeloid-derived suppressor cells accumulation through ENTPD2/CD39L1 in hepatocellular carcinoma. Nature Communications. 2017;8:517. DOI: 10.1038/s41467-017-00530-7
16.Mandl M, Depping R. ARNT is a potential direct HIF-1 target gene in human Hep3B hepatocellular carcinoma cells. Cancer Cell International. 2017;17:77. DOI: 10.1186/s12935-017-0446-2
17.Shneor D, Folberg R, Pe'er J, Honigman A, Frenkel S. Stable knockdown of CREB, HIF-1 and HIF-2 by replication-competent retroviruses abrogates the responses to hypoxia in hepatocellular carcinoma. Cancer Gene Therapy. 2017;24:64-74. DOI: 10.1038/cgt.2016.68
18.Jiao HK, Xu Y, Li J, Wang W, Mei Z, Long XD, et al. Prognostic significance of Cbx4 expression and its beneficial effect for transarterial chemoembolization in hepatocellular carcinoma. Cell Death & Disease. 2015;6:e1689. DOI: 10.1038/cddis.2015.57
19.Li J, Xu Y, Long XD, Wang W, Jiao HK, Mei Z, et al. Cbx4 governs HIF-1alpha to potentiate angiogenesis of hepatocellular carcinoma by its SUMO E3 ligase activity. Cancer Cell. 2014;25:118-131. DOI: 10.1016/j.ccr.2013.12.008
20.Lu J, Wang XZ, Zhang TQ, Huang XY, Yao JG, Wang C, et al. Prognostic significance of XRCC4 expression in hepatocellular carcinoma. Oncotarget. 2017;8:87955-87970. DOI: 10.18632/oncotarget.21360
21.Yao JG, Huang XY, Long XD. Interaction of DNA repair gene polymorphisms and aflatoxin B1 in the risk of hepatocellular carcinoma. International Journal of Clinical and Experimental Pathology. 2014;7:6231-6244. DOI: PMC4203246
22.Dewantoro O, Gani RA, Akbar N. Hepatocarcinogenesis in viral hepatitis B infection: The role of HBx and p53. Acta Medica Indonesiana. 2006;38:154-159. DOI: PMID16953033
23.Moudgil V, Redhu D, Dhanda S, Singh J. A review of molecular mechanisms in the development of hepatocellular carcinoma by aflatoxin and hepatitis B and C viruses. Journal of Environmental Pathology, Toxicology and Oncology. 2013;32:165-175. DOI: 10.1615/JEnvironPatholToxicolOncol.2013007166
24.Liu LP, Hu BG, Ye C, Ho RL, Chen GG, Lai PB. HBx mutants differentially affect the activation of hypoxia-inducible factor-1alpha in hepatocellular carcinoma. British Journal of Cancer. 2014;110:1066-1073. DOI: 10.1038/bjc.2013.787
25.O'Connor JP, Jayson GC. Do imaging biomarkers relate to outcome in patients treated with VEGF inhibitors? Clinical Cancer Research. 2012;18:6588-6598. DOI: 10.1158/1078-0432.CCR-12-1501
26.Park YN, Kim YB, Yang KM, Park C. Increased expression of vascular endothelial growth factor and angiogenesis in the early stage of multistep hepatocarcinogenesis. Archives of Pathology & Laboratory Medicine. 2000;124:1061-1065. DOI: 10.1043/0003-9985(2000)124<1061:IEOVEG>2.0.CO;2
27.Poon RT, Lau CP, Cheung ST, Yu WC, Fan ST. Quantitative correlation of serum levels and tumor expression of vascular endothelial growth factor in patients with hepatocellular carcinoma. Cancer Research. 2003;63:3121-3126. DOI: PMID12810638
28.Jinno K, Tanimizu M, Hyodo I, Nishikawa Y, Hosokawa Y, Doi T, et al. Circulating vascular endothelial growth factor (VEGF) is a possible tumor marker for metastasis in human hepatocellular carcinoma. Journal of Gastroenterology. 1998;33:376-382. DOI: PMID9658317
29.Kim SJ, Choi IK, Park KH, Yoon SY, Oh SC, Seo JH, et al. Serum vascular endothelial growth factor per platelet count in hepatocellular carcinoma: Correlations with clinical parameters and survival. Japanese Journal of Clinical Oncology. 2004;34:184-190. DOI: PMID15121753
30.Poon RT, Ng IO, Lau C, Zhu LX, Yu WC, Lo CM, et al. Serum vascular endothelial growth factor predicts venous invasion in hepatocellular carcinoma: A prospective study. Annals of Surgery. 2001;233:227-235. DOI: PMC1421205
31.Chao Y, Li CP, Chau GY, Chen CP, King KL, Lui WY, et al. Prognostic significance of vascular endothelial growth factor, basic fibroblast growth factor, and angiogenin in patients with resectable hepatocellular carcinoma after surgery. Annals of Surgical Oncology. 2003;10:355-362. DOI: 10.1245/ASO.2003.10.002
32.Poon RT, Lau C, Yu WC, Fan ST, Wong J. High serum levels of vascular endothelial growth factor predict poor response to transarterial chemoembolization in hepatocellular carcinoma: A prospective study. Oncology Reports. 2004;11:1077-1084. DOI: 10.3892/or.11.5.1077
33.Liao X, Yi J, Li X, Yang Z, Deng W, Tian G. Expression of angiogenic factors in hepatocellular carcinoma after transcatheter arterial chemoembolization. Journal of Huazhong University of Science and Technology. Medical Sciences. 2003;23:280-282. DOI: PMID14526434
34.Suzuki H, Mori M, Kawaguchi C, Adachi M, Miura S, Ishii H. Serum vascular endothelial growth factor in the course of transcatheter arterial embolization of hepatocellular carcinoma. International Journal of Oncology. 1999;14:1087-1090. DOI: 10.3892/ijo.14.6.1087
35.Hisai H, Kato J, Kobune M, Murakami T, Miyanishi K, Takahashi M, et al. Increased expression of angiogenin in hepatocellular carcinoma in correlation with tumor vascularity. Clinical Cancer Research. 2003;9:4852-4859. DOI: PMID14581357
36.Guo RP, Zhong C, Shi M, Zhang CQ, Wei W, Zhang YQ, et al. Clinical value of apoptosis and angiogenesis factors in estimating the prognosis of hepatocellular carcinoma. Journal of Cancer Research and Clinical Oncology. 2006;132:547-555. DOI: 10.1007/s00432-006-0097-5
37.Miyahara K, Nouso K, Tomoda T, Kobayashi S, Hagihara H, Kuwaki K, et al. Predicting the treatment effect of sorafenib using serum angiogenesis markers in patients with hepatocellular carcinoma. Journal of Gastroenterology and Hepatology. 2011;26:1604-1611. DOI: 10.1111/j.1440-1746.2011.06887.x
38.Matsubara T, Kanto T, Kuroda S, Yoshio S, Higashitani K, Kakita N, et al. TIE2-expressing monocytes as a diagnostic marker for hepatocellular carcinoma correlates with angiogenesis. Hepatology. 2013;57:1416-1425. DOI: 10.1002/hep.25965
39.Sun XT, Yuan XW, Zhu HT, Deng ZM, Yu DC, Zhou X, et al. Endothelial precursor cells promote angiogenesis in hepatocellular carcinoma. World Journal of Gastroenterology. 2012;18:4925-4933. DOI: 10.3748/wjg.v18.i35.4925
40.Long XD, Yao JD, Yang Q, Huang CH, Liao P, Nong LG, et al. Polymorphisms of DNA repair genes and toxicological effects of aflatoxin B1 exposure. In: Faulkner AG, editor. Aflatoxins: Food Sources, Occurrence and Toxicological Effects. 1. New York: Nova Science Publishers; 2014. pp. 125-156. DOI: 978-1-63117-298-4
41.Niller HH, Ay E, Banati F, Demcsak A, Takacs M, Minarovits J. Wild type HBx and truncated HBx: Pleiotropic regulators driving sequential genetic and epigenetic steps of hepatocarcinogenesis and progression of HBV-associated neoplasms. Reviews in Medical Virology. 2016;26:57-73. DOI: 10.1002/rmv.1864
42.Huang CY, Hsieh FS, Wang CY, Chen LJ, Chang SS, Tsai MH, et al. Palbociclib enhances radiosensitivity of hepatocellular carcinoma and cholangiocarcinoma via inhibiting ataxia telangiectasia-mutated kinase-mediated DNA damage response. European Journal of Cancer. 2018;102:10-22. DOI: 10.1016/j.ejca.2018.07.010
43.Min J, Guo K, Suryadevara PK, Zhu F, Holbrook G, Chen Y, et al. Optimization of a novel series of ataxia-telangiectasia mutated kinase inhibitors as potential radiosensitizing agents. Journal of Medicinal Chemistry. 2016;59:559-577. DOI: 10.1021/acs.jmedchem.5b01092
44.Kew MC. Aflatoxins as a cause of hepatocellular carcinoma. Journal of Gastrointestinal and Liver Diseases. 2013;22:305-310. DOI: PMID24078988
45.Wu XM, Xi ZF, Lu J, Wang XZ, Zhang TQ, Huang XY, et al. Genetic single nucleotide polymorphisms (GSNPs) in the DNA repair genes and hepatocellular carcinoma related to aflatoxin B1 among Guangxiese population. In: Parine NR, editor. Genetic Polymorphisms. Vol. 1. Rijeka, Croatia: InTech; 2017. pp. 97-119. DOI: 10.5772/intechopen.69530
46.Kensler TW, Roebuck BD, Wogan GN, Groopman JD. Aflatoxin: A 50-year odyssey of mechanistic and translational toxicology. Toxicological Sciences. 2011;120(Suppl 1):S28-S48. DOI: 10.1093/toxsci/kfq283
47.Wang JS, Groopman JD. DNA damage by mycotoxins. Mutation Research. 1999;424:167-181. DOI: 10.1016/S0027-5107(99)00017-2
48.Kubo S, Kinoshita H, Hirohashi K, Tanaka H, Tsukamoto T, Shuto T, et al. High malignancy of hepatocellular carcinoma in alcoholic patients with hepatitis C virus. Surgery. 1997;121:425-429. DOI: 10.1016/S0039-6060(97)90313-5
49.Leshets M, Silas YBH, Lehming N, Pines O. Fumarase: From the TCA cycle to DNA damage response and tumor suppression. Frontiers in Molecular Biosciences. 2018;5:68. DOI: 10.3389/fmolb.2018.00068
50.Davis AJ, Chen DJ. DNA double strand break repair via non-homologous end-joining. Translational Cancer Research. 2013;2:130-143. DOI: 10.3978/j.issn.2218-676X.2013.04.02
51.Piciocchi M, Cardin R, Cillo U, Vitale A, Cappon A, Mescoli C, et al. Differential timing of oxidative DNA damage and telomere shortening in hepatitis C and B virus-related liver carcinogenesis. Translational Research. 2016;168:122-133. DOI: 10.1016/j.trsl.2015.08.012
52.Long XD, Ma Y, Huang HD, Yao JG, Qu DY, Lu YL. Polymorphism of XRCC1 and the frequency of mutation in codon 249 of the p53 gene in hepatocellular carcinoma among Guangxi population, China. Molecular Carcinogenesis. 2008;47:295-300. DOI: 10.1002/mc.20384
53.Li LP, Wu W, Li XH, Song SS. The XRCC1 Arg280His gene polymorphism and hepatocellular carcinoma risk: A meta-analysis. Asian Pacific Journal of Cancer Prevention. 2013;14:2033-2036. DOI: PMID23679314
54.Li W, Yang F, Gui Y, Bian J. DNA repair gene XRCC1 Arg194Trp polymorphism and susceptibility to hepatocellular carcinoma: A meta-analysis. Oncology Letters. 2014;8:1725-1730. DOI: 10.3892/ol.2014.2351
55.Long XD, Ma Y, Wei YP, Deng ZL. The polymorphisms of GSTM1, GSTT1, HYL1*2, and XRCC1, and aflatoxin B1-related hepatocellular carcinoma in Guangxi population, China. Hepatology Research. 2006;36:48-55. DOI: 10.1016/j.hepres.2006.06.004
56.Zeng XY, Huang JM, Xu JW, Xu Y, Yu HP, Ji L, et al. Meta-analysis demonstrates lack of a relationship between XRCC1-399 gene polymorphisms and susceptibility to hepatocellular carcinoma. Genetics and Molecular Research. 2013;12:1916-1923. DOI: 10.4238/2013.March.15.5
57.Avadanei ER, Giusca SE, Negura L, Caruntu ID. Single nucleotide polymorphisms of XRCC3 gene in hepatocellular carcinoma–relationship with clinicopathological features. Polish Journal of Pathology. 2018;69:73-81. DOI: 10.5114/pjp.2018.75340
58.Ji RB, Qian YS, Hu AR, Hu YR. DNA repair gene XRCC3 T241M polymorphism and susceptibility to hepatocellular carcinoma in a Chinese population: A meta-analysis. Genetics and Molecular Research. 2015;14:15988-15996. DOI: 10.4238/2015.December.7.11
59.Long XD, Ma Y, Qu DY, Liu YG, Huang ZQ, Huang YZ, et al. The polymorphism of XRCC3 codon 241 and AFB1-related hepatocellular carcinoma in Guangxi population, China. Annals of Epidemiology. 2008;18:572-578. DOI: 10.1016/j.annepidem.2008.03.003
60.Makkoch J, Praianantathavorn K, Sopipong W, Chuaypen N, Tangkijvanich P, Payungporn S. Genetic Variations in XRCC4 (rs1805377) and ATF6 (rs2070150) are not associated with hepatocellular carcinoma in Thai patients with hepatitis B virus infection. Asian Pacific Journal of Cancer Prevention. 2016;17:591-595. DOI: PMID26925648
61.Long XD, Zhao D, Wang C, Huang XY, Yao JG, Ma Y, et al. Genetic polymorphisms in DNA repair genes XRCC4 and XRCC5 and aflatoxin B1-related hepatocellular carcinoma. Epidemiology. 2013;24:671-681. DOI: 10.1097/EDE.0b013e31829d2744
62.Long XD, Yao JG, Zeng Z, Ma Y, Huang XY, Wei ZH, et al. Polymorphisms in the coding region of X-ray repair complementing group 4 and aflatoxin B1-related hepatocellular carcinoma. Hepatology. 2013;58:171-181. DOI: 10.1002/hep.26311
63.Jung SW, Park NH, Shin JW, Park BR, Kim CJ, Lee JE, et al. Polymorphisms of DNA repair genes in Korean hepatocellular carcinoma patients with chronic hepatitis B: Possible implications on survival. Journal of Hepatology. 2012;57:621-627. DOI: 10.1016/j.jhep.2012.04.039
64.Xu Y, Liu AJ, Gao YX, Hu MG, Zhao GD, Zhao ZM, et al. Expression of Ku86 and presence of Ku86 antibody as biomarkers of hepatitis B virus related hepatocellular carcinoma. Digestive Diseases and Sciences. 2014;59:614-622. DOI: 10.1007/s10620-013-2941-1
65.Wang Z, Lin H, Hua F, Hu ZW. Repairing DNA damage by XRCC6/KU70 reverses TLR4-deficiency-worsened HCC development via restoring senescence and autophagic flux. Autophagy. 2013;9:925-927. DOI: 10.4161/auto.24229
66.Li R, Yang Y, An Y, Zhou Y, Liu Y, Yu Q, et al. Genetic polymorphisms in DNA double-strand break repair genes XRCC5, XRCC6 and susceptibility to hepatocellular carcinoma. Carcinogenesis. 2011;32:530-536. DOI: 10.1093/carcin/bgr018
67.Kim E, Li K, Lieu C, Tong S, Kawai S, Fukutomi T, et al. Expression of apolipoprotein C-IV is regulated by Ku antigen/peroxisome proliferator-activated receptor gamma complex and correlates with liver steatosis. Journal of Hepatology. 2008;49:787-798. DOI: 10.1016/j.jhep.2008.06.029
68.Reliene R, Goad ME, Schiestl RH. Developmental cell death in the liver and newborn lethality of Ku86 deficient mice suppressed by antioxidant N-acetyl-cysteine. DNA Repair (Amst). 2006;5:1392-1397. DOI: 10.1016/j.dnarep.2006.06.007
69.Muguruma M, Nishimura J, Jin M, Kashida Y, Moto M, Takahashi M, et al. Molecular pathological analysis for determining the possible mechanism of piperonyl butoxide-induced hepatocarcinogenesis in mice. Toxicology. 2006;228:178-187. DOI: 10.1016/j.tox.2006.08.029
70.Chu L, Zhang X, Wang G, Zhou W, Du Z, Liu A, et al. Serum anti-Ku86: A potential biomarker for early detection of hepatocellular carcinoma. Zhonghua Zhong Liu Za Zhi. 2014;36:123-127. DOI: PMID24796461
71.Wang Z, Yan J, Lin H, Hua F, Wang X, Liu H, et al. Toll-like receptor 4 activity protects against hepatocellular tumorigenesis and progression by regulating expression of DNA repair protein Ku70 in mice. Hepatology. 2013;57:1869-1881. DOI: 10.1002/hep.26234
72.Hsu CM, Yang MD, Chang WS, Jeng LB, Lee MH, Lu MC, et al. The contribution of XRCC6/Ku70 to hepatocellular carcinoma in Taiwan. Anticancer Research. 2013;33:529-535. DOI: PMID23393345
73.Nomura F, Sogawa K, Noda K, Seimiya M, Matsushita K, Miura T, et al. Serum anti-Ku86 is a potential biomarker for early detection of hepatitis C virus-related hepatocellular carcinoma. Biochemical and Biophysical Research Communications. 2012;421:837-843. DOI: 10.1016/j.bbrc.2012.04.099
74.Hsieh YH, Chang WS, Tsai CW, Tsai JP, Hsu CM, Jeng LB, et al. DNA double-strand break repair gene XRCC7 genotypes were associated with hepatocellular carcinoma risk in Taiwanese males and alcohol drinkers. Tumour Biology. 2015;36:4101-4106. DOI: 10.1007/s13277-014-2934-5
75.Long XD, Yao JG, Huang YZ, Huang XY, Ban FZ, Yao LM, et al. DNA repair gene XRCC7 polymorphisms (rs#7003908 and rs#10109984) and hepatocellular carcinoma related to AFB1 exposure among Guangxi population, China. Hepatology Research. 2011;41:1085-1093. DOI: 10.1111/j.1872-034X.2011.00866.x
76.Pascale RM, Joseph C, Latte G, Evert M, Feo F, Calvisi DF. DNA-PKcs: A promising therapeutic target in human hepatocellular carcinoma? DNA Repair (Amst). 2016;47:12-20. DOI: 10.1016/j.dnarep.2016.10.004
77.Song H, Hollstein M, Xu Y. p53 gain-of-function cancer mutants induce genetic instability by inactivating ATM. Nature Cell Biology. 2007;9:573-580. DOI: 10.1038/ncb1571
78.Dong P, Karaayvaz M, Jia N, Kaneuchi M, Hamada J, Watari H, et al. Mutant p53 gain-of-function induces epithelial-mesenchymal transition through modulation of the miR-130b-ZEB1 axis. Oncogene. 2013;32:3286-3295. DOI: 10.1038/onc.2012.334
79.Long XD, Huang HD, Huang XY, Yao JG, Xia Q. XPC codon 939 polymorphism is associated with susceptibility to DNA damage induced by aflatoxin B1 exposure. International Journal of Clinical and Experimental Medicine. 2015;8:1197-1204. DOI: PMC4358568
80.Long XD, Ma Y, Zhou YF, Ma AM, Fu GH. Polymorphism in xeroderma pigmentosum complementation group C codon 939 and aflatoxin B1-related hepatocellular carcinoma in the Guangxi population. Hepatology. 2010;52:1301-1309. DOI: 10.1002/hep.23807
81.Long XD, Ma Y, Huang YZ, Yi Y, Liang QX, Ma AM, et al. Genetic polymorphisms in DNA repair genes XPC, XPD, and XRCC4, and susceptibility to Helicobacter pylori infection-related gastric antrum adenocarcinoma in Guangxi population, China. Molecular Carcinogenesis. 2010;49:611-618. DOI: 10.1002/mc.20630
82.Long XD, Ma Y, Zhou YF, Yao JG, Ban FZ, Huang YZ, et al. XPD Codon 312 and 751 polymorphisms, and AFB1 exposure, and hepatocellular carcinoma risk. BMC Cancer. 2009;9:400. DOI: 10.1186/1471-2407-9-400
83.Roset R, Inagaki A, Hohl M, Brenet F, Lafrance-Vanasse J, Lange J, et al. The Rad50 hook domain regulates DNA damage signaling and tumorigenesis. Genes & Development. 2014;28:451-462. DOI: 10.1101/gad.236745.113
84.Kim JH, Grosbart M, Anand R, Wyman C, Cejka P, Petrini JHJ. The Mre11-Nbs1 interface is essential for viability and tumor suppression. Cell Reports. 2017;18:496-507. DOI: 10.1016/j.celrep.2016.12.035
85.Wang Y, Li M, Long J, Shi XY, Li Q, Chen J, et al. Clinical significance of increased expression of Nijmegen breakage syndrome gene (NBS1) in human primary liver cancer. Hepatology International. 2014;8:250-259. DOI: 10.1007/s12072-013-9500-x
86.Wang Y, Hong Y, Li M, Long J, Zhao YP, Zhang JX, et al. Mutation inactivation of Nijmegen breakage syndrome gene (NBS1) in hepatocellular carcinoma and intrahepatic cholangiocarcinoma. PLoS One. 2013;8:e82426. DOI: 10.1371/journal.pone.0082426
87.Huang MD, Chen XF, Xu G, Wu QQ, Zhang JH, Chen GF, et al. Genetic variation in the NBS1 gene is associated with hepatic cancer risk in a Chinese population. DNA and Cell Biology. 2012;31:678-682. DOI: 10.1089/dna.2011.1421
88.Li J, Dou D, Li P, Luo W, Lv W, Zhang C, et al. PARP-1 serves as a novel molecular marker for hepatocellular carcinoma in a Southern Chinese Zhuang population. Tumour Biology. 2017;39:1010428317706914. DOI: 10.1177/1010428317706914
89.Mao X, Du S, Yang Z, Zhang L, Peng X, Jiang N, et al. Inhibitors of PARP-1 exert inhibitory effects on the biological characteristics of hepatocellular carcinoma cells in vitro. Molecular Medicine Reports. 2017;16:208-214. DOI: 10.3892/mmr.2017.6568
90.Luo Q, Li Y, Deng J, Zhang Z. PARP-1 inhibitor sensitizes arsenic trioxide in hepatocellular carcinoma cells via abrogation of G2/M checkpoint and suppression of DNA damage repair. Chemico-Biological Interactions. 2015;226:12-22. DOI: 10.1016/j.cbi.2014.12.007
91.Chen L, Liu MM, Liu H, Lu D, Zhao XD, Yang XJ. ERCC1 and XRCC1 but not XPA single nucleotide polymorphisms correlate with response to chemotherapy in endometrial carcinoma. OncoTargets and Therapy. 2016;9:7019-7028. DOI: 10.2147/OTT.S110976
92.Hu ZJ, Xue JF, Zhang XY, Shi XS, Zhou H. Relationship between genetic polymorphism of ERCC1 and susceptibility to liver cancer. Zhonghua Liu Xing Bing Xue Za Zhi. 2010;31:1288-1291. DOI: 10.3760/cma.j.issn.0254-6450.2010.11.020
93.Li Y, Ou C, Shu H, Zhao H, Zhu B. The ERCC1-4533/8092, TNF-alpha 238/308 polymorphisms and the risk of hepatocellular carcinoma in Guangxi Zhuang populations of China: Case-control study. Medicine (Baltimore). 2016;95:e5217. DOI: 10.1097/MD.0000000000005217
94.Liu J, Liu Y, Meng L, Ji B, Yang D. Synergistic antitumor effect of sorafenib in combination with ATM inhibitor in hepatocellular carcinoma cells. International Journal of Medical Sciences. 2017;14:523-529. DOI: 10.7150/ijms.19033
95.Ma CQ, Yang Y, Wang JM, Du GS, Shen Q, Liu Y, et al. The aPKCiota blocking agent ATM negatively regulates EMT and invasion of hepatocellular carcinoma. Cell Death & Disease. 2014;5:e1129. DOI: 10.1038/cddis.2014.91
96.Mansoori AA, Jain SK. Molecular links between alcohol and tobacco induced DNA damage, gene polymorphisms and patho-physiological consequences: A systematic review of hepatic carcinogenesis. Asian Pacific Journal of Cancer Prevention. 2015;16:4803-4812. DOI: PMID26163595
97.Gu DL, Chen YH, Shih JH, Lin CH, Jou YS, Chen CF. Target genes discovery through copy number alteration analysis in human hepatocellular carcinoma. World Journal of Gastroenterology. 2013;19:8873-8879. DOI: 10.3748/wjg.v19.i47.8873
98.Huang S, Zhang Y, Zeng T. Effect of ATM-111 (G>A) polymorphism on cancer risk: A meta-analysis. Genetic Testing and Molecular Biomarkers. 2016;20:359-366. DOI: 10.1089/gtmb.2015.0320
99.Vorechovsky I. Mutation analysis of large genomic regions in tumor DNA using single-strand conformation polymorphism. Lessons from the ATM gene. Methods in Molecular Medicine. 2002;68:115-124. DOI: PMID11901497
100.Thorstenson YR, Shen P, Tusher VG, Wayne TL, Davis RW, Chu G, et al. Global analysis of ATM polymorphism reveals significant functional constraint. American Journal of Human Genetics. 2001;69:396-412. DOI: 10.1086/321296
101.Yu L, Liu X, Han C, Lu S, Zhu G, Su H, et al. XRCC1 rs25487 genetic variant and TP53 mutation at codon 249 predict clinical outcomes of hepatitis B virus-related hepatocellular carcinoma after hepatectomy: A cohort study for 10 years' follow up. Hepatology Research. 2016;46:765-774. DOI: 10.1111/hepr.12611
102.Pastukh V, Roberts JT, Clark DW, Bardwell GC, Patel M, Al-Mehdi AB, et al. An oxidative DNA "damage" and repair mechanism localized in the VEGF promoter is important for hypoxia-induced VEGF mRNA expression. American Journal of Physiology. Lung Cellular and Molecular Physiology. 2015;309:L1367-L1375. DOI: 10.1152/ajplung.00236.2015
103.Guo J, Yang J, Li Y. Association of hOGG1 Ser326Cys polymorphism with susceptibility to hepatocellular carcinoma. International Journal of Clinical and Experimental Medicine. 2015;8:8977-8985. DOI: PMC4537974
104.Sakamoto T, Higaki Y, Hara M, Ichiba M, Horita M, Mizuta T, et al. hOGG1 Ser326Cys polymorphism and risk of hepatocellular carcinoma among Japanese. Journal of Epidemiology. 2006;16:233-239. DOI: 10.2188/jea.16.233
105.Wang W, Dang S, Li Y, Sun M, Jia X, Wang R, et al. hOGG1 Ser326Cys polymorphism and risk of hepatocellular carcinoma among East Asians: A meta-analysis. PLoS One. 2013;8:e60178. DOI: 10.1371/journal.pone.0060178
106.Long XD, Yao JD, Yang Q, Huang CH, Liao P, Nong LG, et al. Polymorphisms of DNA repair genes and toxicological effects of aflatoxin B1 exposure. In: Faulkner AG, editor. Aflatoxins: Food Sources, Occurrence and Toxicological Effects. 1st ed. New York: Nova Science Publishers; 2014. pp. 107-124
107.Long XD, Huang HD, Xia Q. The polymorphism of XRCC3 codon 241 and the hotspot mutation in the TP53 gene in hepatocellular carcinoma induced by aflatoxin B1. Journal of Tumor. 2014;2:272-277. DOI: 10.6051/j.issn.1819-6187.2014.02.57
108.Liu YX, Long XD, Xi ZF, Ma Y, Huang XY, Yao JG, et al. MicroRNA-24 modulates aflatoxin B1-related hepatocellular carcinoma prognosis and tumorigenesis. BioMed Research International. 2014;2014:482926. DOI: 10.1155/2014/482926
109.Huang XY, Yao JG, Huang HD, Wang C, Ma Y, Xia Q, et al. MicroRNA-429 modulates hepatocellular carcinoma prognosis and tumorigenesis. Gastroenterology Research and Practice. 2013;2013:804128. DOI: 10.1155/2013/804128
110.Lovric J, Mano M, Zentilin L, Eulalio A, Zacchigna S, Giacca M. Terminal differentiation of cardiac and skeletal myocytes induces permissivity to AAV transduction by relieving inhibition imposed by DNA damage response proteins. Molecular Therapy. 2012;20:2087-2097. DOI: 10.1038/mt.2012.144
111.Kasza Z, Fredlund Fuchs P, Tamm C, Eriksson AS, O'Callaghan P, Heindryckx F, et al. MicroRNA-24 suppression of N-deacetylase/N-sulfotransferase-1 (NDST1) reduces endothelial cell responsiveness to vascular endothelial growth factor A (VEGFA). The Journal of Biological Chemistry. 2013;288:25956-25963. DOI: 10.1074/jbc.M113.484360
112.Chan MC, Hilyard AC, Wu C, Davis BN, Hill NS, Lal A, et al. Molecular basis for antagonism between PDGF and the TGFbeta family of signalling pathways by control of miR-24 expression. The EMBO Journal. 2010;29:559-573. DOI: 10.1038/emboj.2009.370
113.Zhou Q, Anderson C, Zhang H, Li X, Inglis F, Jayagopal A, et al. Repression of choroidal neovascularization through actin cytoskeleton pathways by microRNA-24. Molecular Therapy. 2014;22:378-389. DOI: 10.1038/mt.2013.243
114.Jeggo PA, Lobrich M. Contribution of DNA repair and cell cycle checkpoint arrest to the maintenance of genomic stability. DNA Repair (Amst). 2006;5:1192-1198. DOI: 10.1016/j.dnarep.2006.05.011
115.Qin G, Kishore R, Dolan CM, Silver M, Wecker A, Luedemann CN, et al. Cell cycle regulator E2F1 modulates angiogenesis via p53-dependent transcriptional control of VEGF. Proceedings of the National Academy of Sciences of the United States of America. 2006;103:11015-11020. DOI: 10.1073/pnas.0509533103
116.Herbert SP, Odell AF, Ponnambalam S, Walker JH. Activation of cytosolic phospholipase A2-{alpha} as a novel mechanism regulating endothelial cell cycle progression and angiogenesis. The Journal of Biological Chemistry. 2009;284:5784-5796. DOI: 10.1074/jbc.M807282200
117.Ingber DE, Prusty D, Sun Z, Betensky H, Wang N. Cell shape, cytoskeletal mechanics, and cell cycle control in angiogenesis. Journal of Biomechanics. 1995;28:1471-1484. DOI: 10.1016/0021-9290(95)00095-X
118.Gillardon F, Moll I, Meyer M, Michaelidis TM. Alterations in cell death and cell cycle progression in the UV-irradiated epidermis of bcl-2-deficient mice. Cell Death and Differentiation. 1999;6:55-60. DOI: 10.1038/sj.cdd.4400455
119.Ashimori N, Zeitlin BD, Zhang Z, Warner K, Turkienicz IM, Spalding AC, et al. TW-37, a small-molecule inhibitor of Bcl-2, mediates S-phase cell cycle arrest and suppresses head and neck tumor angiogenesis. Molecular Cancer Therapeutics. 2009;8:893-903. DOI: 10.1158/1535-7163.MCT-08-1078
120.Diaz G, Engle RE, Tice A, Melis M, Montenegro S, Rodriguez-Canales J, et al. Molecular signature and mechanisms of hepatitis D virus-associated hepatocellular carcinoma. Molecular Cancer Research. 2018;16:1406-1419. DOI: 10.1158/1541-7786.MCR-18-0012
121.Zhou ZQ, Zhao JJ, Chen CL, Liu Y, Zeng JX, Wu ZR, et al. HUS1 checkpoint clamp component (HUS1) is a potential tumor suppressor in primary hepatocellular carcinoma. Molecular Carcinogenesis. 2018. DOI: 10.1002/mc.22908 [Ahead of print]
122.Broustas CG, Hopkins KM, Panigrahi SK, Wang L, Virk RK, Lieberman HB. RAD9A promotes metastatic phenotypes through transcriptional regulation of anterior gradient 2 (AGR2). Carcinogenesis. 2018. DOI: 10.1093/carcin/bgy131 [Ahead of print]
123.Chen Q, Wang L, Jiang M, Huang J, Jiang Z, Feng H, et al. E2F1 interactive with BRCA1 pathway induces HCC two different small molecule metabolism or cell cycle regulation via mitochondrion or CD4+T to cytosol. Journal of Cellular Physiology. 2018;233:1213-1221. DOI: 10.1002/jcp.25988
124.Gramantieri L, Chieco P, Giovannini C, Lacchini M, Trere D, Grazi GL, et al. GADD45-alpha expression in cirrhosis and hepatocellular carcinoma: Relationship with DNA repair and proliferation. Human Pathology. 2005;36:1154-1162. DOI: 10.1016/j.humpath.2005.07.017
125.Majano PL, Garcia-Monzon C, Lopez-Cabrera M, Lara-Pezzi E, Fernandez-Ruiz E, Garcia-Iglesias C, et al. Inducible nitric oxide synthase expression in chronic viral hepatitis. Evidence for a virus-induced gene upregulation. The Journal of Clinical Investigation. 1998;101:1343-1352. DOI: 10.1172/JCI774
126.Shimoda K, Mori M, Shibuta K, Banner BF, Barnard GF. Vascular endothelial growth factor/vascular permeability factor mRNA expression in patients with chronic hepatitis C and hepatocellular carcinoma. International Journal of Oncology. 1999;14:353-359. DOI: 10.3892/ijo.14.2.353
127.Si M, Lang J. The roles of metallothioneins in carcinogenesis. Journal of Hematology & Oncology. 2018;11:107. DOI: 10.1186/s13045-018-0645-x
128.Lezina L, Spriggs RV, Beck D, Jones C, Dudek KM, Bzura A, et al. CD40L/IL-4-stimulated CLL demonstrates variation in translational regulation of DNA damage response genes including ATM. Blood Advances. 2018;2:1869-1881. DOI: 10.1182/bloodadvances.2017015560
129.Tehrani SS, Karimian A, Parsian H, Majidinia M, Yousefi B. Multiple functions of long non-coding RNAs in oxidative stress, DNA damage response and cancer progression. Journal of Cellular Biochemistry. 2018;119:223-236. DOI: 10.1002/jcb.26217
Written By
Xi-Dai Long, Zhou-Ximao Long, Xiao-Ying Huang, Jin-Guang Yao, Qiang Xia and Yan Deng
Reviewed: 15 October 2018Published: 13 November 2018
Open access peer-reviewed chapter
