Chapter 1: "Permanent Maxillary and Mandibular Incisors"\n
Chapter 2: "The Permanent Maxillary and Mandibular Premolar Teeth"\n
Chapter 3: "Dental Anatomical Features and Caries: A Relationship to be Investigated"\n
Chapter 4: "Anatomy Applied to Block Anaesthesia"\n
Chapter 5: "Treatment Considerations for Missing Teeth"\n
Chapter 6: "Anatomical and Functional Restoration of the Compromised Occlusion: From Theory to Materials"\n
Chapter 7: "Evaluation of the Anatomy of the Lower First Premolar"\n
Chapter 8: "A Comparative Study of the Validity and Reproducibility of Mesiodistal Tooth Size and Dental Arch with the iTero Intraoral Scanner and the Traditional Method"\n
Chapter 9: "Identification of Lower Central Incisors"\n
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She was born in Zonguldak, Turkey, on February 14, 1974; she is married and has two children. She graduated in 1997 from the Ankara University, Faculty of Dentistry, Ankara, Turkey. She aquired her PhD in 2004 from the Gazi University, Faculty of Dentistry, Department of Endodontics, Ankara, Turkey, and she is still an associate professor at the same department. She has published numerous articles and a book chapter in the areas of Operative Dentistry, Esthetic Dentistry and Endodontics. 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Preimplantation embryo development follows a series of critical events. These events start at gametogenesis, formation of mature gametes, and lasts until parturition. Male and female gametes are derived from primordial germ cells (PGCs) by the processes of spermatogenesis and oogenesis, respectively. PGCs have unique properties of gene expression, epigenetics, morphology and behaviour. Once the PGCs undergo mitosis, spermatogenesis and oogenesis progress differently. In spermatogenesis, spermatogonia undergo mitosis starting at puberty until death and each primary spermatocyte produces four spermatids at the end of meiosis. In oogenesis, PGCs differentiate into oogonia, they enter meiosis and arrest until puberty. Unlike meiosis II in spermatogenesis, secondary oocyte does not complete meiosis II until fertilisation. With completion of meiosis II, each oogonia produce a single viable oocyte [1].
At fertilisation, the oocyte completes meiosis and the fertilised oocyte is called the zygote. Oocyte and sperm nuclei fuse resulting in syngamy (Figure 1). The zygote undergoes a series of cleavage divisions, forming two‐cell, four‐cell, eight‐cell morula and blastocyst stages [2] (Figure 1). During cleavage stage divisions, programming of maternal and paternal chromosomes takes place to create the embryonic genome (embryonic genome activation, EGA) and to start the preimplantation embryo development. If the EGA fails, the development does not continue because of the inability of the embryo to have cellular functions [3]. This activation is initiated by the degradation of maternal nucleic acids, specific RNAs stored in oocytes, proteins and other macromolecules [4]. Upon EGA, which starts at the two‐cell stage in mouse and four‐ to eight‐cell stage in human [5], remarkable reprogramming of expression occurs in the preimplantation embryo. These reprogramming events are controlled by DNA methylation, histone acetylation, transcription, translation and miRNA regulation [6]. Therefore, the development of preimplantation embryos includes continuous molecular, cellular and morphological events. These events would eventually form a multilineage embryo that has a capability to implant and continue the foetal development.
Schematic diagram outlining the main stages of preimplantation embryo development. Fertilisation followed by syngamy, cleavage divisions results in two, three, four, and so on cell embryos which eventually form the morula and the blastocyst.
In this chapter, different factors affecting gene expression during preimplantation embryo development will be discussed. Epigenetic factors, focusing on methylation profiles, of gametes and preimplantation embryos will be reviewed. The effects of noncoding RNAs on gene expression will be thoroughly evaluated.
For a normal developing embryo, the expression of both maternal and paternal genes is required. An intense epigenetic change occurs upon fertilisation to establish pluripotency [7]. Although there are a number of post‐translational modifications within chromatin including acetylation, ubiquitination, SUMOylation and phosphorylation; methylation of histone lysine and arginine residues is the main focus in preimplantation embryos.
Methylation and chromatin modification not only play crucial roles in determining the transcriptional state but also are capable of determining the transcriptional repression [8–10]. The mechanism leading to the changes in methylation is not well established, but it has been suggested that the reprogramming takes place by either passive or active demethylation. Indirect pathways of demethylation are associated with DNA repair [11–14]. Two main stages, PGCs and preimplantation embryos, are important in the regulation by methylation.
In mammals (human, bovine, rat, pig and mouse), the zygote undergoes genome‐wide demethylation [15–17] with the exception of imprinted genes [18]. The male pronucleus of the zygote undergoes selective demethylation due to the loss of DNA replication leading to asymmetric methylated sister chromatids [15, 16, 19, 20]. These events start following the sperm decondensation in humans and in mouse with some variations [17, 21, 22]. The female pronucleus of the zygote remains highly methylated at this stage [17, 21, 22]. Demethylation of the maternal genome starts with the first cleavage divisions [19, 23, 24]. By the morula stage, the mouse preimplantation embryos become undermethylated. Polarisation and compaction of individual blastomeres start at around eight‐cell stage of the developing embryo. Many factors are involved in these processes including E‐cadherin (CDH1), partitioning defective homologue 3 (PARD3), PARD6B and protein kinase C zeta [25–27].
The blastocyst stage embryo has a fluid‐filled cavity and two cell populations consisting of inner cell mass (ICM) and trophectoderm (TE). All the blastomeres are believed to be totipotent in cleavage embryos until four‐ to eight‐cell stage since these cells form both the ICM and TE lineage [28]. ICM develops into epiblast, whereas TE forms the extraembryonic tissues such as placenta. ICM is composed of pluripotent cells that have the capacity to develop into any cell type of the foetus. Transcriptional and epigenetic events strictly regulate these differentiation events. A number of transcriptional factors play a crucial role in blastocyst formation. These include caudal type homeobox 2 (CDX2) for TE specification, octamer 3/4 (OCT4) and NANOG for the establishment of ICM pluripotency [29–31]. CDX2 is extensively expressed in eight‐ and 16‐cell stage and it is expressed only in TE cells of the blastocyst [32]. Although OCT4 and NANOG are also expressed broadly at eight‐ and 16‐cell stage embryos, they are only expressed in ICM in blastocysts [32]. A number of transcription factors are required for blastocyst formation. Embryos lacking CDX2 expression cannot form blastocoel cavity but they have the ability to implant [30]. Lack of OCT4 or NANOG expression causes failure of ICM and the development of these embryos is arrested at the blastocyst stage [31, 32]. TEAD4 is another transcription factor that has a role in blastocyst transition in which the lack of TEAD4 nuclear localisation impairs TE‐specific transcriptional programme in inner blastomeres [33]. Furthermore, the aberrant expression of TCFAP2C transcription factor also leads to embryonic arrest during morula to blastocyst transition [34] and Klf5 mouse‐mutant embryos arrest at the blastocyst stage [35].
The remethylation process starts shortly after implantation [16, 22, 23, 36]. This de novo methylation occurs asymmetrically, such that ICM is hypermethylated possibly due to the Dnmt3b methylase [37], whereas TE remains hypomethylated due to the active demethylation by enzyme catalysis and passive demethylation [11, 14, 22]. Alteration of the methylation profiles in embryos has been shown to cause alterations of ICM and TE differentiation. Variations of the H3 arginine 26 residue (H3R26me) were shown to lead to changes of TE and ICM differentiation of a blastomere [38].
X‐chromosome inactivation is an epigenetic phenomenon in which the activity of X chromosomes is strictly regulated to equalise X‐chromosome expression and gene dosage between males and females and relative to autosome chromosomes [39]. For correct development, X‐chromosome dosage compensation is crucial. The inactivation of X chromosome occurs in at least two phases: initiation and maintenance. X‐inactivation mouse model systems have shown that the inactivation of X chromosome takes place during early embryogenesis of the female embryo by undergoing transcriptional silencing of genes along the X chromosome [40]. In human preimplantation embryos, it has been shown that the reduced expression of X chromosomes in females ensures the dosage compensation [41]. LncRNA XIST expression activates the X‐chromosome inactivation by engaging proteins functioning in chromatin remodelling [3, 42]. With the advanced technologies, including single‐cell RNA sequencing, it has emerged that lncRNAs XACT and XIST are expressed on the active X chromosome in the early human preimplantation embryos [43]. Furthermore, the expression of these two RNAs has never been shown to overlap. Introducing XACT into heterologous systems caused the accumulation of Xist RNA in cis and therefore it may be involved in the control of XIST association to chromosome in cis and may temper its ability of silencing. It is also possible that XACT functions in balancing the X‐chromosome inactivation at the early stages of preimplantation embryo development [43, 44]. Recently, the dosage compensation was shown to be driven by a CAG promoter of a new Xist allele (Xist(CAG)) [45]. Furthermore, Xist(CAG) upregulation in preimplantation embryos showed variation depending on the parental origin and the paternal expression was suggested to be preferentially inactivated with the paternal Xist(CAG) transmission [45].
In germ cells, methylation is maintained in a sex‐specific manner. Methylation in PGCs diminishes as they migrate to the gonads. Studies suggest that in females, remethylation occurs after birth when the oocytes are in the process of development. When demethylation is completed, the PGCs either enter mitosis in males or arrest at meiosis in females [46].
Reprogramming of the methylation in the embryo is necessary for parent‐specific expression of genes [14]. Gene expression varies during preimplantation embryo development due to these reprogramming events and appropriate gene expression determines the survival of the embryo [6]. Recently, short noncoding RNAs, microRNAs (miRNAs) and long noncoding RNAs (lncRNA) have gained importance in their potential function to affect numerous pathways by targeting multiple genes [47, 48].
MiRNAs are a large family of short noncoding RNAs between 17 and 25 nucleotides (nt) in length [49]. MiRNAs were first identified in Caenorhabditis elegans over two decades ago [50] and since then many have been identified in multiple organisms, such as worms, flies, fish, frogs, mammals and plants, by molecular cloning and bioinformatics [51]. Most miRNA sequences are conserved among a wide range of mammalians [52], though there are some that differ from each other only by a single nucleotide [53]. The conserved miRNA sequences among different species can be distinguished by the nomenclature such that when only the first three letters differ this indicates the same sequence in different species, that is, hsa‐miR‐145 in Homo sapiens and mmu‐miR‐145 in Mus musculus [54].
MiRNAs have been shown to be of great importance in a wide variety of biological processes involving cell cycle regulation, apoptosis, cell differentiation, imprinting, homeostasis and development, including limb development [55], morphogenesis of lung epithelial [56], embryonic angiogenesis [57], formation of hair follicle and proliferation of T‐cell [58, 59]. They play key roles in regulating transcriptional and post‐transcriptional gene silencing in many organisms by targeting mRNAs for translational inhibition, cleavage, degradation or destabilisation [53, 60–64]. Each miRNA has multiple mRNA targets that may regulate up to 30% protein‐coding genes and shape protein production from hundreds to thousands of genes [65–67]. MiRNAs recognise their targets through base pairing of the complementary sequence of their seed sequence (2–8 nt of miRNAs) within the open reading frame (ORF) and 3′untranslated region (UTR) of target mRNA [68]. Although the targets of miRNAs are not fully known, bioinformatics studies show a range of possible target genes [69]. The functional activities and the predicted/observed targets of miRNAs can be identified using miRNA databases. These databases can be accessed using the following URL: (
MiRNA biogenesis involves multiple important steps. MiRNAs are first transcribed from genomic DNA into primary miRNA (pri‐miRNA), which contains a stem‐loop structure, by RNA polymerase II. These pri‐miRNAs are then processed by Drosha, which is a 30–160 kDa protein with one dsRNA‐binding and two catalytic domains [70]. In the presence of DGCR8, both strands of the hairpin are cut generating a pre‐miRNA product of approximately 70 nt in size [71]. These pre‐miRNAs are carried from the nucleus into the cytoplasm by Exportin‐5 (Exp5), which is a nucleocytoplasmic transporter in karyopherin family that has binding sites for pre‐miRNAs in the presence of RAs‐related nuclear protein (Ran) and guanosine triphosphate (GTP) [72, 73]. These miRNAs are further cleaved by cytoplasmic RNase endonuclease, Dicer, making 21–22 nt double‐stranded structure. Although one of the strands is usually degraded, both strands of the pre‐miRNA may be associated with Argonaute (Ago)‐protein‐containing complex and they are mediated by RISC/miRNP (RNA‐induced silencing complex/mi‐ribonucleoprotein) to form single‐stranded mature miRNAs. MiRNAs associated with RISC mainly target mRNAs and they either inhibit their translation or cause degradation of mRNA that results in reduced protein synthesis [70, 74].
Studies showed that processing of miRNAs by Dicer was vital and any defects, such as deletion of Dicer in the developing animals, caused aberrations [75, 76]. Lack of Dicer in Drosophila germ line stem cells postponed the G1/S phase transition [77], suggesting that miRNAs may be vital for stem cells to bypass this checkpoint. Reduced and disorganised spindles, incorrect chromosome alignment and defects in gastrulation were observed with the Dicer‐mutant oocytes in mouse and in C. elegans, respectively [50, 78]. Injection of miR‐430 in zebrafish and C. elegans partially repaired the gastrulation, retinal development and somatogenesis [78]. Dicer deletion in zebrafish, mouse and hippocampal initiated problems in the nervous system and led to the inability of forming mature miRNAs that resulted in variations of brain morphogenesis and differentiation of neurons [79, 80]. Although the axis formation and early differentiation of maternal‐zygotic Dicer‐mutant zebrafish and mouse embryos were normal, they still triggered defects in somitogenesis, morphogenesis that affected the brain formation, gastrulation, heart development and apoptosis in limb mesoderm, respectively [78, 81–83]. Apoptosis was enhanced in the developing limb mesoderm of Dicer null mouse [84]. Dicer deficiency mainly led to embryo death in mouse around embryonic day 7.5 [50, 78, 85] and in zebrafish [86] that may indicate the importance of miRNA‐mediated gene silencing at maternal to zygotic transition.
Complete loss of Dicer1 in somatic cells of mouse reproductive tract not only showed reduced expression of miRNAs but also caused the female mice to become infertile with compromised oocyte and embryo integrity [50, 87]. Dicer‐deficient male mice were shown to have poor proliferation of spermatogonia. Loss of Dicer1 in the germ line of male mice (homozygote Dicer1) led to decreased fertility due to abnormal spermatogenesis. The number of germ cells was reduced with abnormal spermatids, abnormal phenotype of spermatocytes with condensed nucleus, abnormal sperm motility and mutant testes with Sertoli tubules [88]. Studies suggest that the transfer of maternal cytoplasmic Dicer disguised the early abnormal phenotypes [78, 89].
Knock‐out of Ago2 in mouse embryonic fibroblasts and haematopoietic cells caused decreased levels of mature miRNAs [61, 90, 91]. Ago2‐deficient oocytes were observed to develop the mature oocytes with abnormal spindles and chromosomes were not able to unite properly with reduced expression levels of miRNAs (more than 80%). Loss of Ago2 function leads to embryo death around embryonic day 9.5 in mouse [92].
The expression of miRNAs in preimplantation embryos has been mainly studied by knock‐out experiments, by cloning experiments and by identifying individual miRNAs by microarray analysis and real‐time polymerase chain reaction [93]. The expression studies have been carried out using animal models and tissues, cultured cells; that is, cancer cells and human embryonic stem cells; and mouse/bovine/human gametes and embryos. Human embryonic stem cells, which are derived from the inner cell mass of an embryo at the blastocyst stage and are characterised by their ability of self‐renewal and multipotency, are the key in gene expression research since the access of human embryos is difficult and these cells are one of the closest representations of human embryos. Studying miRNA expression in stem cells not only gives insight into potential miRNAs expressed in human embryos but also may show the important role of miRNAs in the stem cell functioning [94].
MiRNA expression has been observed as early as oogenesis and spermatogenesis in mouse, bovine and human [95, 96]. Differences in the miRNA expression have been observed between immature and mature oocytes that may represent the natural turnover and indicate that each embryonic stage is defined by a specific miRNA. Similar miRNA expression profiles in mature mouse oocytes and early developing embryos indicate that at these stages the zygote has maternally inherited miRNAs [50]. Similar to oocyte, sperm carries a range of miRNAs. Approximately 20% of these miRNAs are located in the nuclear or perinuclear part of the sperm indicating that these miRNAs are transferred to the zygote at the time of fertilisation [97]. It was suggested that the sperm‐borne miRNAs may down‐regulate the maternal transcripts in mammals. However, when this hypothesis was tested using microarray analysis, it was shown that none of these miRNAs in the sperm have significant importance since all of them were already present in the oocytes (meiosis II) [98].
Multiple miRNAs were involved in the formation of germ cell layers. MiR‐290, which was expressed at different levels during preimplantation embryo development of mouse embryos, had a negative effect on the germ cell and mesoderm differentiation in the mouse ES cells via targeting Nodal inhibitors [99]. In zebrafish, however, miR‐290 cluster played an important role in regulating the mesoderm induction [100]. Therefore, it is not clear if miR‐290 has an inhibitory effect on the mesoderm differentiation. Other miRNAs have been shown to have an effect in mesoderm differentiation in zebrafish, such as miR‐15 and miR‐16 [100], which were also expressed in mouse preimplantation embryos [50].
Mainly, the same miRNAs are expressed during the cleavage divisions of the embryo in mouse and bovine. However, their expression levels often vary during these stages. In murine embryos, the level of miRNA expression is reduced by as much as 60% between one‐ and two‐cell stages. At the end of four‐cell stage, mouse embryos have approximately twice as much miRNA compared to the two‐cell stage embryo. This implies that the maternally inherited miRNAs degrade at this stage and the EGA starts between the one‐cell and four‐cell stages [50]. Even though the synthesis and degradation of miRNAs coexists during the preimplantation embryo development in mice, the overall miRNA expression increased towards the blastocyst stage [101].
More than 700 miRNAs have been identified in humans [87, 95, 96, 102]. The level of expression for the majority of these miRNAs stayed the same between the oocyte and the blastocyst stage [87]. More than 50% of the miRNAs expressed in human oocytes and blastocysts were shown to be involved in tumourigenesis, that is, let‐7 family, miR‐19a, miR‐21 and miR‐34 [103–109].
In the last few years, in addition to short noncoding RNAs, the lncRNA have gained importance in their roles to affect gene expression. The mammalian genomes consist of long intergenic noncoding RNAs (lincRNAs) that have been suggested to take a role in the regulation of pluripotency during preimplantation embryo development [110]. Human pluripotency transcripts 2, 3 and 5 (HPAT2, HPAT3 and HPAT5) were reported to adjust the pluripotency and ICM formation in preimplantation embryos. Furthermore, HPAT5 was shown to interact with let‐7 family of miRNAs [110].
Implantation of embryos involves complex mechanisms and many different genetic and physiological factors are involved during the process. Developing preimplantation embryo must have a good coordinated interaction with the maternal uterine endometrium. LncRNAs were shown to be differentially expressed in endometrial tissues obtained from pigs with pregnancy and non‐pregnancy with two lncRNAs, TCONS_01729386 and TCONS_01325501, with potential roles in implantation [111].
In Western world, approximately 1% of children are born with assisted reproductive technology (ART) treatments. The infertile couples have the best possibility to conceive a child with these treatments. Although these techniques have been considered to be safe in terms of foetal and post‐natal development [112, 113], there is an increased risk for morbidities, especially imprinting disorders [114]. Furthermore, the global gene expression profiles vary due to in vitro culture of zygotes [115, 116] and in vitro fertilisation processes [117]. Following in vitro culture, apoptotic and morphogenetic pathways have shown to be altered [118].
Intra‐cytoplasmic sperm injection (ICSI), one of the widely used ART techniques, provides infertile couples with sperm motility problems a great chance to have a baby. ICSI is a unique process in which the sperm is injected into the ooplasm [119]. However, ICSI bypasses a number of physiological processes that would normally take place. These embryos derived from ICSI were shown to be cleaved at a slower rate. Furthermore, a reduced number of embryos become hatched with a fewer number of cells and the calcium oscillations are shorter with different patterns [120]. Mice embryos generated by ICSI were shown to be obese and have anomalies of the organs [121].
Normal development of preimplantation embryos involves complex mechanisms. For a normal developing embryo, the expression of both maternal and paternal genes is required. Several factors are involved in the regulation of parental genes in preimplantation embryos. Epigenetic modifications are one of the most important factors that are involved in the regulation of gene expression during preimplantation embryos. Extensive research studies have been performed throughout the years to establish the methylation profiles of the mammalian gametes and embryos. In the more recent years, the importance of noncoding RNAs in the regulation of genes has become clear. A handful of studies have been performed to analyse the expression of microRNAs, which have been shown to regulate mRNAs that encode up to 30% human protein‐coding genes. The expression of miRNAs has been observed in mouse, bovine and human gametes and embryos. Furthermore, in the last couple of years, expression of long noncoding RNAs and their roles in embryonic development and implantation have been investigated. The extensive research studies have provided crucial understanding of the development of preimplantation embryos and the regulation of gene expression, and with the advancing technologies more molecular studies will help to comprehend the mechanisms better.
The malignant transformation results in a specific rearrangement of metabolic processes called metabolic reprogramming of tumor cell. The altered metabolism causes a selective advantage to a transformed cell by facilitating its survival in a harsh environment and promoting the spread of tumor cells within the body.
Malignant cells very effectively adapt to high proliferation rate, metastasis, and invasion. Several molecular mechanisms were pointed out to drive such metabolic adaptation of cancer cells. The critical aspects of metabolic reprogramming in tumor cells substantially contribute to the Warburg effect [1], an increased catabolism of glucose to lactate in the presence of oxygen [2]. The altered metabolism of tumors results in elevated biosynthesis of macromolecules such as proteins, carbohydrates, and lipids and, in consequence, supports high proliferation rate of malignant cells [3].
In particular, the regulation of mitochondrial processes in cancer cells differs from normal counterparts, and it may be specific to the stage of tumor [4]. Therefore, cancer cells are sensitive to drugs that disrupt energy homeostasis, such as Metformin (1,1-dimethylbiguanide, Met) [5].
A generic drug, Metformin, has been widely used for treatment of diabetes mellitus in humans. However, it exerts pleiotropic effect in human organism. In particular, a great interest has been paid to Met, since retrospective analyses demonstrated that it significantly decreased the relative risk of cancer incidence in diabetic patients when compared with patients treated with other drugs. Clinical trials confirmed the epidemiological observations that Met exerted anticancer effects in humans [6]. It has been established that Met inhibits proliferation of various neoplastic cell lines in vitro, including breast, prostatic, colon, gastric, and cervical cancers [7, 8]. Currently, there is an intense ongoing research focused on molecular mechanisms behind these effects, since the implications of Met action in tumor cell are not completely understood [9].
To date, several molecular mechanisms were reported to play critical role in anticancer activity of Met. In particular, it was established that Met may affect energy metabolism of cancer cells by inhibition of complex I of mitochondrial electron transport chain (ETC) in mitochondria, which results in adenosine-5′-triphosphate (ATP) depletion and remodeling of the network of biosynthetic processes within the cell [9]. Met may act as an anticancer drug through the activation of the main energy regulator within the cell, adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) [7], and inhibition of mechanistic target of rapamycin complex-1 (mTORC1) [10] in tumor cells. Some of the pharmacological effects of Met seem to be independent of its action on glycemia homeostasis. Several reports demonstrated that treatment of tumor cells with Met results in cell cycle perturbations and apoptosis [11, 12]. The intracellular targets affected by Met were comprehensively reviewed by Ikhlas and Ahmad [9] and Pierotti et al. [13].
Along with the advent of human papillomavirus (HPV) vaccines, the primary prevention of cervical cancer has become more successful, but cervical malignancy still remains the significant cause of cancer mortality in women worldwide. Currently, chemotherapy using cytostatic drugs (mainly cisplatin, cis-dichlorodiammineplatinum (II)) is still the primal regimen, despite low specificity and substantial toxicity in patients [14].
Aerobic glycolysis has been recognized as the most common metabolic feature of malignant cells. The alterations in metabolism of cancer cells combined with the overexpression of oncogenes (c-Myc) and transcription factors (hypoxia-inducible factor 1a, HIF 1a) confer a great advantage to malignant cells to avoid apoptosis induced by reactive oxygen species (ROS). In this study we focused on the effects of Met on metabolism of metastatic cervical tumor cells. Based on recent data, we reported that Met inhibited glycolytic phenotype of aggressive cervical cancer cells by regulation of expression of oncogenes and their downstream proteins, which led to cellular death. Furthermore, Met regulated mitochondrial metabolism, especially via supplementation of tricarboxylic acid cycle (TCA cycle, Krebs cycle) with pyruvate and glutamine. Met, by targeting epithelial and mesenchymal markers of tumor cells, alleviated invasive properties of cervical cancer cells.
This review summarizes recent findings on Met and cervical cancer underscoring new implications of this drug in regulation of peculiar metabolism of tumor cells. We discuss new perspectives about targeting specific alterations in cervical tumor metabolic pathways using Met.
A growing evidence suggests that the screening for molecular targets for anticancer therapeutic treatments should take into account the existing differences in tumor cell phenotypes. Therefore, the metabolic effects exerted by Met were studied using SiHa cells (American Type Culture Collection, ATCC designation HTB-35) originating from aggressive cervical tumor, which acquired malignant characteristics [15]. The regulation of apoptosis pathways in HTB-35 (SiHa) cells highly reflects the specificity of cervical tumor in vivo [16]. HTB-35 cells, even unstimulated with cytokines, have mesenchymal-like characteristics, especially high vimentin expression, along with enhancement of cell scattering and ability to move [17]. Another cell line, C-4I cells (ATCC, designation CRL1594) with epithelial phenotype, was derived from primary in situ tumor [18]. HTB-34 cells (ATCC designation MS751) were isolated from metastatic site in lymph node [19]. HTB-35, C-4I and HTB-34 are human squamous cell cervical carcinoma lines and it is worth noting that squamous cell cancer is the most common cervical cancer and accounts for almost 80% of cervical carcinomas in patients [14]. HeLa human cervical cancer cells (ATCC designation CCL2), which have been extensively used in mechanistic studies, expressed epithelial traits and were derived from adenocarcinoma [8].
The reliance on glucose supply is linked to the aggressiveness of malignant cells. Such reprogrammed metabolism makes migrating cancer cells more robust and independent of environmental conditions. The dysregulation of glucose metabolism is caused by alterations in functioning of several oncogenes. Malignant cells may gain metabolic plasticity by upregulation of only few oncogenes, such as c-Myc, p53, phosphoinositide 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) [20]. Additionally, the activation of transcription factors, such as HIF-1α, makes malignant cells more resistant to hypoxia (decreased oxygen level in microenvironment), which is one of the main factors affecting tumor growth [20]. The activation of HIF-1α is one of the crucial processes that promote glycolysis to generate ATP along with the decrease of mitochondrial pathways’ activity in aggressive tumors. What is more, the migrating tumor cells may avoid oxidative stress by relying on glucose catabolism. As a result, tumor cells have higher chance to survive detachment from extracellular matrix (ECM), whereas normal cells undergo programmed death due to anoikis in the absence of attachment to ECM [21]. Following detachment from primary tumor bed and transportation to plasma and lymph, malignant cells may spread within the body and form secondary tumors. Therefore, the reprogrammed metabolism plays a crucial role in facilitating tumor metastasis.
We found that Met may regulate glycolysis in aggressive cervical cancer cells. The glycolytic phenotype of tumor cells is triggered mainly by a master regulator HIF-1α and its downstream proteins. Our study showed that Met alleviated the hypoxia-induced activation of HIF-1α, which was followed by decreased expression of HIF-1α downstream protein effectors in HTB-35 cells, as demonstrated in [22]. In particular, Met downregulated GLUT transporters (solute carrier family 2 member receptors, SLC2A), specifically GLUT1 and GLUT3. Additionally, Met inhibited the regulatory enzymes of the glycolytic pathway, hexokinase 2 (HK2), bifunctional enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 (PFKFB4), pyruvate kinase (PKM), and lactate dehydrogenase (LDH) (Figure 1). Met exerted greater effect on regulatory proteins in HTB-35 cells exposed to decreased oxygen level in the air than normal conditions.
Metformin inhibits glycolytic phenotype of cervical carcinoma cells (↑—activation, Ⱶ—inhibition) [11, 12, 21, 22].
Recent studies have reported that overexpression of c-Myc oncogene plays a significant role in the formation of cervical cancer. The enhanced expression of c-Myc is also of particular relevance to promoting invasive phenotype of cancer cells. What is more, the upregulated c-Myc may collaborate with HIF to effectively induce glucose and glutamine consumption in tumor cells. As a result, mitochondrial oxidative phosphorylation decreases. In particular, the upregulated c-Myc enhances glutamine catabolism in tumor cells, since the oncogene controls glutaminase (GLS) expression [23]. As measured using qPCR analysis, Met decreased c-MYC transcript level in HTB-35 cells [22], which was in compliance with inhibition of GLS protein expression [11]. The treatment of cervical tumor cells with Met decreased mRNA level for another c-Myc downstream protein, CCND1 (cyclin D1), which regulates cell cycle progression [22]. Zhang et al. [24] reported that Met caused a substantial decrease of cyclin D1 expression in bladder cancer cells. The overexpression of oncogene cyclin D1 is positively correlated with chemotherapeutic resistance and apoptosis avoidance in squamous cell cancers [23]. The inhibition of CCND1 expression in aggressive cervical tumor cells resulted in enhanced apoptosis [22].
Met triggered another pro-apoptotic mechanism in cervical carcinoma cells via regulation of Bcl-2 (B-cell lymphoma 2) protein family members’ expression [22]. Bcl-2 proteins are key players in the regulation of mitochondrial-dependent programmed cell death. The activation of BAX protein leads to disruption of mitochondrial membrane potential and apoptosis, whereas Bcl-2 acts as an apoptotic suppressor. The counterbalancing pro- and anti-apoptotic effectors of Bcl-2 protein family play a crucial role in the regulation of the mitochondrial apoptotic cascade within the cell and constitute another important apoptotic checkpoint [25]. However, the disturbance of BAX/Bcl-2 pathway may result in the resistance to apoptosis by inducing compensatory mechanisms, thereby influencing the efficacy of some therapeutic regimens [26]. The exposition of cervical tumor cells to Met significantly upregulated BAX transcript. It was found that the expression of BAX under hypoxic conditions was greater than in normoxia [22]. Additionally, Met downregulated transcript for BCL-2 in HTB-35 cells in both, normoxic and hypoxic conditions.
The study using cervical cancer cells with metastatic phenotype cells showed that the downregulation of oncogenes/downstream regulatory proteins, together with the upregulation of pro-apoptotic BAX/Bcl-2, elucidated mitochondrial-dependent apoptosis in tumor cells. The obtained data suggest that Met was highly effective in facilitating cell death in cervical tumor cells [22], since it exerted its effect targeting independent events controlling mitochondrial apoptosis including the induction of ROS [11], the regulation of Bcl-2 protein family expression, and downregulation of cyclin D1. It should be emphasized that Met induced cell death solely in tumor cells, without causing detrimental effects to normal cells [11].
The reprogrammed metabolism of tumor cells not only meets high energetic demands but also provides intermediates for intensive proliferation. Therefore, glycolysis and mitochondrial oxidative phosphorylation may operate simultaneously in cancer cells. Many tumors may even switch between these pathways accordingly to the current requirements. Recent studies showed that most cancer cells have metabolically efficient mitochondria to provide intermediates for biosynthesis, generate reductive power (nicotinamide adenine dinucleotide phosphate, NADPH), and restore cofactor pool (e.g., nicotinamide adenine dinucleotide, NADH). In highly proliferating cancer cells, mitochondrial TCA cycle is active enough to sustain the biochemical reactions. Currently, the precise regulation of anabolic pathways and keeping their activities at adequate level is thought to play a key role in determination of “flexible” metabolic phenotype of cancer cells that enables their rapid division. Moreover, oxidative phosphorylation (OXPHOS) may represent a significant contribution to energy generation within malignant cell. On the other hand, inevitable products of OXPHOS are ROS and oxidative stress due to ROS overproduction may kill tumor cells [27].
It was demonstrated that the process of detachment of migrating squamous cancer cells from extracellular matrix (ECM) results in reprogramed metabolism toward glycolysis, particularly by PDH complex inhibition and following suppression of glucose respiration in mitochondria. Such metabolic phenotype of tumor cell enables efficient production of energy without excessive ROS generation. On the other hand, the stimulation of PDH activity may lead to increased anoikis sensitivity and attenuation of metastatic potential of cancer cells [28].
We found that Met may precisely regulate PDH metabolic checkpoint in cervical tumor cells (Figure 2). Met had great potency to activate oxidative decarboxylation of pyruvate to acetyl-CoA in HTB-35 cells expressing invasive phenotype, and it occurred via activation of PDH complex [11]. PDH complex plays a determinant role in the overall glucose disposal within the cell, since it funnels mitochondrial TCA cycle instead of lactate formation in cytosol. PDH activity is precisely regulated via covalent modification by the action of specific enzyme pyruvate dehydrogenase kinase (PDK). Several PDK activators were found to expand potent antitumor effect, also in cervical tumor HeLa cells [29]. We showed in aggressive cervical cancer HTB-35 cells that Met suppressed both PDK activity and the expression of gene encoding tumor-specific isoenzyme PDK1 [22]. This finding may have practical implications, since the screening strategy for PDK inhibitors should recognize the specificity among the PDK isoenzymes in order to avoid side effects in vivo [30]. Under hypoxic conditions inside tumors, the activation of HIF-1α decreases mitochondrial metabolism, which prevents the cell from oxidative stress and helps cancer cells avoid apoptosis [20, 23]. Our study showed that in aggressive cervical cancer cells Met counteracted these metabolic alterations by inhibiting PDK1, which is at the same time HIF-1α prime downstream effector. Furthermore, Met downregulated PDK1 gene expression also in normoxia [22].
Metformin regulates mitochondrial metabolism of cervical carcinoma cells (↑—activation, Ⱶ—inhibition) [11, 13, 22, 27, 30].
In tumor cells that have functional mitochondria, the generation of oxidative stress may become an important therapeutic target [27, 30]. The imbalance of metabolic regulation and the resulting overproduction of ROS in mitochondrial ETC cause oxidative stress, which, at some point, becomes toxic to cancer cells, and that escalation of ROS elicits apoptosis-inducing factors and triggers death program through multiple mechanisms. In compliance, it has been newly reported that Met significantly increased ROS level, altered apoptosis-associated signaling, and induced cell death in human gastric adenocarcinoma cells [31] and human cervical cancer HeLa cells [32]. We found that in HTB-35 cervical cancer cells, Met caused excessive generation of mitochondrial ROS and elicited apoptosis [11, 22]. As shown in [22], the effect of Met was specific to tumor cells, and the formation of mitochondrial ROS was not affected in normal cells exposed to Met.
Met concomitantly targeted cytosolic glycolysis and mitochondrial pathways in HTB-35 cells, which increased apoptosis and suppressed survival of cervical tumor cells under normoxic and hypoxic conditions [22].
Glutamine may provide precursors to feed TCA cycle under limited flux of pyruvate from cytosolic glycolysis within tumor cells. The facilitated use of glutamine is a significant metabolic adaptation of cancer cell, besides enhanced glucose catabolism, and it provides intermediates sufficient for intensive biosynthesis and energy production [20]. Glutaminase (GLS) is a key regulator of glutamine entry to TCA [33], and the inhibition of the enzyme may suppress tumor cell growth [25].
As shown in [11], the exposition of cervical cancer cells with invasive phenotype to Met downregulated the expression of GLS, thereby protecting mitochondrial anabolism from additional carbon supply for synthesis of macromolecules. Additionally, the effect of Met on GLS expression was specific toward cervical cancer cells, and in normal cells drug did not change the expression of the enzyme [11].
Glutamine entry to tumor cell not only improves carbon supply for macromolecules buildup, but it also replenishes the pool of cellular NADPH, since the conversion of malate to pyruvate catalyzed by malic enzyme 1 (ME1) is accompanied by the reduction of NADP+ (Figure 2). NADPH is used for biosynthesis, but it also plays a significant role in the antioxidant protection of tumor cell by reducing glutathione molecule. Met downregulated expression of ME1 and alleviated generation of NADPH in cells, which, in conditions of limited supplementation of HTB-35 cells with glucose (suppressed expression of GLUTs), resulted in hampering of biosynthesis and alleviation of ROS detoxification [11, 22].
Furthermore, Met treatment caused acute drop in ATP concentration in HTB-35 cells. This is in compliance with data obtained by Parker et al. [34] who demonstrated that non-small cell lung cancer (NSCLC) cells may be uniquely sensitized to metabolic stresses by the action of other biguanide, phenformin (1-(diaminomethylidene)-2-(2-phenylethyl)guanidine). The inhibition of ATP generation may block biosynthesis in cervical tumor cells which results in restraining of cell proliferation.
The facilitated fatty acid (FA) de novo synthesis together with upregulated glycolysis was recognized as one of the prime metabolic alterations in such tumor cells [35]. The enhanced FA biosynthesis meets high demands of rapidly proliferating malignant cells (generating components for cell membranes and signaling molecules). We found that Met decreased unsaturated lipid content in aggressive cervical cancer cells (Figure 2). The mechanism of Met action included downregulation of regulatory enzyme elongase 6 (ELOVL6), which catalyzes elongation of fatty acid molecule. Met also suppressed stearoyl-CoA desaturase (SCD1), which controls desaturation of FA. It was shown by Fritz et al. [36] that pharmacologic inhibition of SCD1 activity impaired unsaturated FA synthesis, which resulted in decreased proliferation of both androgen-sensitive and androgen-resistant prostate cancer cells. The treatment of cervical cancer cell lines [22, 37] with Met decreased cervical tumor cell proliferation, but Met did not affect the growth of normal cells [11].
Emerging data indicate that the enhanced activity of enzymes regulating lipid de novo synthesis may contribute to activation of EMT process in tumor cells [36]. The activation of EMT program in epithelial cancer cells facilitates tumor progression, invasion, and metastasis. It has been shown in independent studies that Met inhibits EMT in various cancer cell lines [8, 37]. Recently, it has been reported that Met reversed EMT phenotype induced with transforming growth factor beta 1 (TGF-β1) in breast, lung, and cervical cancer cells by targeting the mechanisms regulating the expression of E-cadherin. The exposition of tumor cells to Met resulted in suppression of their metastatic properties [8, 38].
In our study, EMT process was induced upon 48 h incubation of cervical cancer cells with 10 ng/mL of cytokine TGF-β1, as described in detail in [17]. HTB-35 cells, even unstimulated, expressed mesenchymal-like characteristics, and the incubation with TGF-β further enforced expression of mesenchymal marker, vimentin, along with enhancement of cell scattering and ability to move [17]. The study showed that Met was an effective suppressor of mesenchymal phenotype and, in particular, downregulated vimentin in HTB-35 cells (Figure 3). Recently, it was reported by Laskov et al. [39] that Met downregulated the expression of vimentin in endometrial cancers in vitro and in vivo in diabetic patients. The incubation of cervical cancer cell lines with Met reduced cells’ ability to move, as shown using functional scratch test in C4-I and HTB-35 cells stimulated with TGF-β1 [17]. Mechanistic study revealed that Met inhibited the expression of transcription factors Snail-1, ZEB-1, and Twist-1. These mesenchymal markers facilitate EMT progress in cervical cancer cells.
Metformin inhibits TGF-β1-induced EMT phenotype of cervical carcinoma cells (↑—activation, Ⱶ—inhibition) [8, 17, 40].
Cheng and Hao [8] proposed another mechanism of Met action in cervical carcinoma cells via inhibition of mTOR/p70s6k signaling pathway and downregulation of glycolytic regulatory protein pyruvate kinase, isozyme M2 (PKM2), in HeLa cell line.
In order to clarify the molecular action of Met in cervical tumor cells with aggressive characteristics, the effect of the drug was tested in the hypoxic conditions. In cervical cancers, hypoxia and concomitant enhanced lactate formation result in acidification of microenvironment, which may promote the ability of metastatic cells to rapidly spread in tissue [41]. In such conditions, the activation of HIF1α induces its downstream protein carbonic anhydrase IX (CAIX). By regulation of tumor milieu pH, CAIX acts as a survival factor protecting malignant cells against enhanced acidification of microenvironment. As a result, lactate damages adjacent normal cells and does not harm tumor cells [42]. Due to its relevant role in cell invasion, CAIX was proposed as a potential therapeutic target, also in cervical cancers [41, 42]. We showed that the exposition of HTB-35 cells to Met under hypoxia suppressed HIF-1α, which resulted in decreased transcription of CAIX gene, thereby alleviating invasive properties of cervical malignant cells [17].
Recently, numerous beneficial activities of Met were reported. Met was shown to improve cardiovascular outcomes in humans [43], and the ability of Met to extend life-span in mammals has attracted great attention [44]. Emerging data indicate that Met may be applied as adjuvant in therapies aiming at combating diseases with high mortality rate, also in cervical cancer [45]. The clinical benefits of the use of Met in gynecologic oncology in humans were reviewed by Irie et al. [46] and Imai et al. [47]. Met also reduced the incidence of endometrial tumors and improved survival of patients with diagnosed local or advanced endometrial cancer [48]. Several clinical trials showed the potential of Met to elicit apoptosis in the uterus and prostate cancers in humans [49].
The potential pathological effects of Met have been well studied in long term in human population. One of the most undesirable effects in the context of peculiar metabolic alterations of cancer cell is the enhanced generation of lactic acid caused by biguanides. In fact, the application of phenformin (1-(diaminomethylidene)-2-(2-phenylethyl)guanidine) was associated with a much higher risk of lactic acidosis in patients, than Metformin. Therefore, the former drug was withdrawn from clinical use. Currently, the contraindication for the use of Met in patients is renal failure, since this group has greater risk of lactic acidosis. However, the concerns over lactic acidosis were shown to be largely unfounded, unless kidney disease was advanced. Yet, based on the recent data, Met can be safely used in patients with mild renal dysfunction, provided that patients are monitored appropriately [43, 50].
The exposition of aggressive cervical cancer cells to Met restrained the function of HIF-1α master regulator and downregulated HIF-1α downstream glycolytic genes. Met also downregulated glycolytic phenotype of HTB-35 cells through inhibition of oncogene c-MYC expression, which resulted in impairment of metabolic plasticity of cervical tumor cells, especially via downregulation of GLS.
Met precisely regulated PDH and GLS metabolic checkpoints in cervical tumor cells. In particular, in tumor cells Met targeted supplementation of mitochondrial pathways in pyruvate by downregulation of PDK1 gene expression and decreasing PDK activity. As a result, Met effectively enhanced TCA cycle flux in normoxic and hypoxic conditions. The downregulation of GLS and ME1 resulted in decreased regeneration of NADPH, the factor essential both for biosynthesis and cell protection against oxidative stress. The metabolic alterations of mitochondrial pathways caused by Met caused excessive generation of ROS which led to apoptosis. In cervical cancer cells, Met additionally induced apoptosis via upregulation of pro-apoptotic BAX protein expression and by downregulation of cyclin D1, oncogene c-MYC downstream protein. Met exerted its pro-apoptotic effect both in normal and decreased oxygen availability. This aspect of Met action may be important when designing anticancer therapies targeting cells in hypoxic milieu inside solid tumors.
It is also important to highlight another cellular mechanism of Met action, namely, the suppression of EMT process in cervical tumor cells. EMT seems implicated into invasiveness and metastasis of cancer, and Met was able to inhibit EMT pathways. In cervical tumor cells stimulated with TGF-β1 as well as in unstimulated ones, Met decreased the expression of the main mesenchymal marker vimentin and reduced motility of cells. In addition, Met downregulated adaptive enzyme CAIX in tumor cells under hypoxia. CAIX promoted migration of malignant cells and acted as an important survival factor, and thus it has recently been proposed as therapeutic target in cervical cancers. Met might be considered as a potential factor targeting CAIX to hamper cervical tumor invasiveness.
These findings provide a new insight into regulation of glycolysis and mitochondrial pathways in cervical tumor cells using nontoxic and well-studied drug, Metformin, indicating the future prospect about utilization of this molecule in clinical oncological routine. The identification and targeting of specific alterations in tumor metabolic pathways may constitute a sole basis to design new precise therapeutic strategies in cervical malignancy. To date, very few innovative therapies against cervical malignancy are being tested in clinical trials; thus more specific and effective intervention is highly required.
The artworks were prepared using elements from Servier Medical Art.
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