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Interaction of Mitochondrial and Epigenetic Regulation in Hepatocellular Carcinoma

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Victoria Chagoya de Sánchez, Enrique Chávez, Gabriela Velasco- Loyden, María Guadalupe Lozano-Rosas and Alejandro Rusbel Aparicio-Cadena

Submitted: April 6th, 2018 Reviewed: July 3rd, 2018 Published: November 5th, 2018

DOI: 10.5772/intechopen.79923

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Hepatocellular carcinoma (HCC) is a pathology preceded mainly by cirrhosis of diverse etiology and is associated with uncontrolled dedifferentiation and cell proliferation processes. Many cellular functions are dependent on mitochondrial function, among which we can mention the enzymatic activity of PARP-1 and sirtuin 1, epigenetic regulation of gene expression, apoptosis, and so on. Mitochondrial dysfunction is related to liver diseases including cirrhosis and HCC; the energetic demand is not properly supplied and mitochondrial morphologic changes have been observed, resulting in an altered metabolism. There is a strong relationship between epigenetics and mitochondrion since the first one is dependent on the correct function of the last one. There is an interest to improve or to maintain mitochondrial integrity in order to prevent or reverse HCC; such is the case of IFC-305 that has a beneficial effect on mitochondrial function in a sequential model of cirrhosis-HCC. In this model, IFC-305 downregulates the expression of PCNA, thymidylate synthase, HGF and its receptor c-Met and upregulates the cell cycle inhibitor p27, thereby decreasing cell proliferation. Both effects, improvement of mitochondria function and reduction of tumor proliferation, suggest its use as HCC chemoprevention or as an adjuvant in chemotherapy.


  • hepatocellular carcinoma
  • cell cycle
  • cell proliferation
  • mitochondria
  • epigenetics
  • IFC-305

1. Introduction

Hepatocellular carcinoma (HCC) represents 80% of the primary liver cancer and, in minor proportion, bile duct cancer and angiosarcoma of the blood vessels in the liver, but all of them have a poor prognosis. HCC is a major cause of cancer-related deaths globally. The incidence of HCC is increasing and has been rising in the last few decades [1]. The HCC is a complex pathology associated in 80–90% with chronic liver diseases like cirrhosis of diverse etiologies. Cirrhosis is a chronic degenerative disease of the hepatic parenchyma characterized by an inflammation process that leads to liver fibrogenesis. This process induces the loss of liver architecture and a diminution of functional parenchyma, which over time changes the environment of the cells resulting in chromosomal instability. The cause of cirrhosis transformation into HCC is not well known, but chromosomal instability could be an important factor for HCC generation in cirrhotic patients. The main problem of this pathology is the lack of early detection, recurrence of tumors following resection [2], and there are no effective therapies. To understand this complex pathology, it is convenient to have some knowledge of the structure and functions of the liver. Therapeutic options for HCC are very limited, and the incidence is very similar to the death rate per year. Only in the early stage of the disease, there are some approved therapies such as tumor ablation, surgical resection, and liver transplantation, but in advanced stages, when most patients are diagnosed, these treatments are not recommended. There is an average of 5-year survival below 20% with these therapies [3]. In intermediate and advanced stage-HCC, the approved options are transcatheter arterial chemoembolization (TACE) and the multi-kinase inhibitor, sorafenib. TACE therapy could extend survival to 2 years [3]. Sorafenib extends survival of patients with advanced stage disease for only 3 months, and this medication causes considerable adverse effects and offers no symptom palliation [4]. There are other several clinical trial efforts focused on therapies involving multiple signaling pathways, most commonly related to tyrosine-kinase growth factor receptors, but they have inferior survival benefits and several adverse effects. Immunotherapy has demonstrated some efficacy, but, in general, molecular characterization to find effective treatments of HCC is needed.

The liver is the largest internal and heterogeneous organ in the body constituted by different kinds of cells like hepatocytes, endothelial cells, cells of the bile duct, Kupffer cells, hepatic stellate cells (HSC), oval cells and pit cells [5]. The liver is an organ highly irrigated by the portal venous system and blood is distributed by the hepatic sinusoids and the hepatic artery [6]. About 80% of the liver cells are hepatocytes, and are epithelial cells that form cords with high metabolic activity and contain a complete set of organelles: mitochondria, peroxisomes, lysosomes, Golgi complex and a well-organized cytoskeleton [7]. The space between cords of hepatocytes and the endothelium is called the space of Disse. Endothelial cells constitute the wall of the hepatic sinusoids and are separated from the parenchymal cells by the space of Disse. They possess pores or fenestrae that permit the exchange of fluids [8]. These cells show endocytic activity and secrete several mediators such as interleukin-1 (IL-1), interleukin-6 (IL-6), interferon, and nitric oxide as paracrine modulators. Kupffer cells are the fixed macrophages of the liver that can migrate along sinusoids. Their main function is an immunomodulatory one [9]. Pit cells are intrahepatic leucocytes with natural killer cell activity [10] and exert a cytotoxic activity toward tumor and virus-infected cells [11]. HSC, also known as lipocytes, fat storing cells, perisinusoidal cells, and vitamin A storing cells, are quiescent in normal conditions. When they are activated, they play an essential role in the synthesis and degradation of the extracellular matrix (ECM) proteins and fibrogenic cytokines, like hepatocyte growth factor (HGF), insulin growth factor (IGR), transforming growth factor-β (TGF-β), and, consequently, induce cirrhosis. Biliary epithelial cells participate in the formation of bile; they are transported to the bile ducts or Canals of Hering. These cells have the potential to become oval cells [7]. The cell-free hepatic tissue represents 20% of the liver volume and constitutes the ECM located in the Disse space. The ECM contains structural proteins like collagen of different types, glycoproteins, fibronectin, tenascin, laminin, entactin, and perlecan. Their function is to maintain the hepatic architecture and the organization of the entire organ. Hepatocytes contribute with 80–90% of the synthesis of liver collagen, which is degraded by metalloproteinases (MMPs) [12]. The liver has multiple functions needed for its own metabolism and for other organs; it participates intensely in the intermediary metabolism that occurs mainly in hepatocytes and is connected with the nutrients of the diet, reaching from the portal circulation, that is, in carbohydrates, proteins, and lipid metabolism. The liver also generates purines and pyrimidines for its own use and their distribution to other tissues in the form of adenosine, inosine, and hypoxanthine [13]. It also synthetizes and secretes plasma proteins and participates in the biotransformation of endogenous and exogenous compounds.

Previously, we have demonstrated that adenosine is a metabolic modulator of glucose and lipids in the liver and adipose tissue [14]. This molecule also modulates in vivo the energy charge in the liver [15]. The nucleoside adenosine is a substance with multiphysiological effects in different tissues, the central nervous system, and cardiovascular system; it is responsible for the modulation of the immune response and acts as metabolic regulator. Its action could be autocrine, paracrine, and endocrine; its metabolism is very active with a high turnover and a very short half-live. Adenosine presents circadian variations in the rat, which correlated with energetic homeostasis of the cell, modulation of membrane structure and function, cell proliferation, and genetic expression by regulating physiological methylation [16]. Exogenous adenosine administration to normal rats showed some pharmacological effects, like increased ATP levels simultaneous to a decrease in ADP and AMP, resulting in an increase of the energy charge of the liver [14]. Also, in the liver of fasted rats, adenosine induces an enhancement of glycogen synthesis [16] and an inhibition of fatty acid oxidation by inhibiting the extramitochondrial acyl CoA synthase and decreasing the plasma ketone bodies [17] These findings allowed us to demonstrate in vivo the Atkinson hypothesis of metabolism regulation by energy charge [18].

The redox state of the cell in different compartments, calculated by the NAD+/NADH (NAD+ and NADH nicotinamide adenine dinucleotide, oxidized and reduced) system, has been shown to be a key point in the control of metabolism [19]. Adenosine administration induces mitochondrial oxidation and promotes the oxidized state in the cytosol and mitochondria in the presence of fatty acid oxidation inhibition, which is induced by the nucleoside. It has been reported that adenosine modulates vasodilatation and vasoconstriction in the hepatic vessels controlling blood flow from the hepatic artery [20]. All these results observed in normal animals led us to test the effects of the nucleoside in several models of acute hepatotoxicity: one induced with ethanol [21], the second with cycloheximide, and the third with carbon tetrachloride (CCl4). Although the toxic mechanism of each one is different, they yielded a similar response generating a fatty liver that was prevented by adenosine [21, 22, 23]. In this way, the nucleoside, through different mechanisms, protects the liver against acute toxicity.

Continuous acute hepatotoxicity results in chronic liver injury with subsequent cirrhosis, with accumulation of ECM proteins, mainly collagen type I [24], accompanied by a deficient degradation of deposited collagen [25]. These conditions will induce a change in liver architecture with loss of its function. This is a complex process, for which no effective treatment has been developed yet. To study the effects of adenosine in this process, a model of cirrhosis induced in rats with CCl4 was developed, in which two conditions were tested: prevention during cirrhosis development and reversion once it is already established [26, 27]. The simultaneous administration of adenosine partially blocked the stimulated collagen synthesis induced by the hepatotoxin, maintained high levels of hepatic collagenase activity, resulting in 50% diminution of fibrosis [26]. The effect of the nucleoside was clearly observed also in the reversion model; it was tested in well-established cirrhosis after 10 weeks of CCl4 administration. Five weeks after suspension of the toxin, animals were treated with saline or adenosine, the saline group increased the cirrhotic characteristics but the group of animals treated with the nucleoside revealed blocked fibrogenesis, increased collagen degradation and normalized collagen types ratio, promoted hepatocyte proliferation, accelerated normalization of liver function, and decreased oxidative stress. These results suggest adenosine as a potential therapeutic agent in the treatment of chronic hepatic disease.

The transfer of an interesting research finding to a clinical setting is complicated, but in collaboration with Dr. Francisco Hernández Luis from the National Autonomous University of Mexico’s School of Chemistry, we prepared several adenosine derivatives that were tested in the CCl4 induced cirrhosis. The aspartate of adenosine, named IFC-305, showed interesting results [28]; beneficial effects in structure and functional recovery were obtained with a fourfold lower dose of this adenosine derivative because it has a longer half-life. The hepatoprotective mechanism of IFC-305 on fibrogenesis was investigated by means of DNA microarrays analysis [29], showing that the expression of 413 differential genes deregulated in cirrhosis tended to be normalized by IFC-305 treatment. Fibrogenic genes, such as TGF-β, collagen type I, fibronectin I, increased their expression in cirrhotic groups, and IFC-305 diminished their expression supporting the antifibrogenic action of the compound. These results highly suggest a diminution of chromosomal instability. With the increased understanding in chromatin organization of the eukaryote genome at genetic and epigenetic levels and remembering the previously commented role of adenosine on physiological methylations, a possible epigenetic mechanism of the IFC-305 could participate in the obtained results. Global changes in DNA methylation, 5-hydroxymethylation and histone H4 acetylation were decreased in cirrhosis and after the IFC-305 treatment the normal values were recuperated. In contrast, the promoter of Col1a1 gene is hypomethylated in cirrhosis but gains DNA methylation upon treatment with IFC-305, correlating with a decrease of Col1a1 transcript and protein level, showing that the treatment restores globally and specifically epigenetic modifications [30]. The microarray analysis also showed modification of immunity genes which where explored in the CCl4 model; it was found that the IFC-305 compound reduced inflammatory cytokines and increased the anti-inflammatory ones like IL-10, supporting the modulation of the macrophage phenotypes M1 and M2 [31].


2. Hepatocytes proliferation in cirrhosis and cancer, modulation by IFC-305

The liver is an organ with regenerative capacity. Partial hepatectomy or diverse stimuli promote proliferation of parenchymal and non-parenchymal cells in order to recover the liver mass and architecture. This process is regulated by cell cycle proteins, cytokines, growth factors, and matrix remodeling [32].

In acute liver injury, there is a classic wound healing process in which inflammation triggers scar formation that is subsequently resolved to enable regeneration of the damaged hepatic parenchyma. However, when there is a chronic liver injury, the normal regenerative process is impaired, and instead a net deposition of fibrillar collagen is predominant [33].

Cirrhosis is characterized by a decrease in hepatocyte proliferation, in part, because liver cells have a limited regenerative capacity restricted by telomere length. After several rounds of replication, telomeres reach a critically short length that induces cell cycle arrest, senescence, and apoptosis of hepatocytes. Telomere shortening also activates DNA repair pathways leading to chromosomal fusions and instability [34]. During cirrhosis-activated HSC, inflammatory cells secrete proliferative and angiogenic cytokines that contribute to a proliferative condition milieu, including: HGF, vascular endothelial growth factor (VEGF), and IL-6 [33]. This proliferative milieu could stimulate the proliferation of altered hepatocytes carrying mutations of cell cycle checkpoint genes or could select genetically altered clones, promoting HCC [34].

Among the principal cell cycle checkpoints that are generally altered in HCC are the tumor suppressor p53 and Rb proteins. p53 is implicated in cell cycle control, DNA repair, apoptosis, and regulates different metabolic pathways [35, 36]. p53 is frequently mutated in HCC (28–50%) and core proteins from hepatitis B and C viruses can repress p53 activity [36]. The pRB protein is implicated in the progression from G1 into S phase. The Rb pathway is disrupted in more than 80% of human HCC [34]. Gankyrin binds Mdm2 promoting proteasomal degradation of p53 and pRb. Both gankyrin and Mdm2 proteins are frequently overexpressed in human HCC [34, 35]. p53 is also implicated in the stimulation of ATP production by oxidative phosphorylation (OXPHOS). p53 also decreases glycolysis and cellular reactive oxygen species (ROS) production by inducing a protein called TP53-induced glycolysis and apoptosis regulator (TIGAR). TIGAR blocks glycolysis by degrading fructose-2,6-bisphosphate. This inhibition redirects glucose-6-phosphate into the pentose phosphate pathway, which increases NADPH production increasing the antioxidant defenses. The inactivation of p53 should decrease OXPHOS and increase glycolysis and ROS production in cancer cells [37].

It has been demonstrated that IFC-305 is able to stimulate hepatocytes proliferation in CCl4-induced cirrhotic liver through the upregulation of proliferating cell nuclear antigen (PCNA), HGF, and p53, with an increase in energy and preservation of mitochondrial function [38].

On the other hand, in a sequential model of cirrhosis-HCC induced by diethylnirosamine (DEN), IFC-305 caused a tumor reduction, and this protective effect was associated with decreased cell proliferation in the HCC stage. This effect was associated with a decreased expression of PCNA, thymidylate synthase, HGF and its receptor c-Met, and the induction of the cell cycle inhibitor p27. IFC-305 also induced a diminution of gankyrin expression contributing to restoring p53 protein expression to control levels [39].

How could the same compound IFC-305 have opposing effects on proliferation in normal versus transformed hepatocytes? These could be mediated partly by a differential expression of the HGF-c-Met pathway driven by IFC-305 treatment, and the dual role of HGF/c-Met in cirrhosis and liver tumorigenesis. HGF expression is restricted to cells of mesenchymal origin, whereas the receptor c-Met is expressed in epithelial and endothelial cells. HGF is implicated in cell proliferation, survival, morphogenesis, cell motility, and metastasis. This pathway plays a critical role in tissue protection and regeneration. It has been used as a therapeutic agent in fibrosis of different organs. The protective actions of HGF are associated with promotion of cell proliferation, migration, and morphogenesis that would help tissues reorganization [40]. Its protective role is also related to its anti-inflammatory action and its regulation of the cellular redox state, driven by upregulation of the antioxidant enzymes and glutathione reduced (GSH), as well as by repression of two major pro-oxidant systems: NADPH oxidase and/or Cyp2E1 [41]. Nevertheless, the HGF/c-Met pathway in HCC contributes to tumor development by stimulating cell proliferation, invasion, and metastasis [40]. We observed that, in the cirrhotic liver induced by CCl4, the hepatoprotector IFC-305 incremented HGF expression [38], which could have a protective role in the regenerative capacity of the liver. On the other hand, in DEN-induced HCC, the IFC305 treatment downregulated HGF and c-Met expression, which contribute to liver tumorigenesis reduction [39]. HGF and c-Met can be potentiated by ROS in hepatoma cells [41, 42]. It was described that, in the sequential model of cirrhosis-HCC with DEN, there are dysfunctional mitochondria and the administration of IFC-305 restored the mitochondrial function and regulated parameters implicated in metabolism, as well as the mitochondrial dynamics modified by DEN intoxication [43]. Therefore, the IFC-305 could be suppressing expression of HGF via the improvement of mitochondrial redox in DEN carcinogenesis. On the other hand, the restoration by IFC-305 treatment of the p53 protein expression in CCl4-induced cirrhosis and in DEN-induced carcinogenesis, among other effects, could contribute to the restoration of ATP production by OXPHOS and to the decrease of ROS production. However, the exact molecular mechanism by which IFC-305 causes different effects on hepatocytes proliferation in cirrhosis and HCC requires further clarification.


3. Mitochondrial alterations in the HCC: the effect of the IFC-305 compound

Mitochondria are responsible for energy metabolism in eukaryotic cells; they generate ATP through oxidative phosphorylation. In addition, an important part of the ATP synthesis is the donation of electrons by the tricarboxylic acids chain (TCA) to the electron transport chain (ETC), constituted by five complexes (I-V), NADH enters complex I and generates NAD+, and complex V forms ATP. Mitochondria regulate the energetic state, the redox state, and the metabolism of the cells, being able to generate the epigenetic intermediaries becoming the main therapeutic target of many kinds of cancer [44].

As a response to stress, the cells acquire a metabolic adaptation, which is an important area of research due to its relationship with different illnesses [45]. In chronic liver diseases like cirrhosis, energetic deficiency and alterations in energy parameters have been demonstrated independently of their etiology [46]. Otto Warburg suggested that mitochondria from tumor cells supply energy through glycolytic flow due to lack of oxygen or genetic-epigenetic alterations that affect oxidative metabolism [47]. Mitochondrial dysfunction is implicated in metabolic reprogramming in HCC. The increased ROS production and the reduced ATP generation may contribute to the HCC malignancy [48]. Metabolic alterations may decrease the levels of acetyl CoA, which also plays an important role as modulator of gene expression [49]. In experimental models, including the CCl4-induced cirrhosis, mitochondrial dysfunction has been demonstrated because impaired mitochondrial respiration and ATP decreased levels have been observed [50, 51]. A metabolic adaptation in response to the ATP diminished levels is increased glycolysis [51]. A consequence of oxidative stress in chronic liver diseases is the decrease in metabolic flux, which includes alterations in the TCA enzymes, such as isocitrate dehydrogenase (IDH), which can produce oncometabolites when it undergoes mutations [52].

The redox state can be represented by the NAD+/NADH ratio, which is regulated by the ETC. Several enzymes depend on NAD+ like sirtuin-1 (Sirt-1), a member of deacetylases, and poly (ADP-ribose) polymerase-1 (PARP-1). A Sirt-1 substrate is the peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC-1α), which is upregulated in HCC and is responsible for orchestrating mitochondrial biogenesis, favoring accumulation of defective mitochondria [44]. On the other hand, PARP-1 modulates the transcription and DNA repair; however, in HCC, it is upregulated and is considered a hallmark of cancer [53]. The over-regulation of both enzymes in HCC may deplete the NAD+ that can be related to loss of mitochondrial membrane potential (ψm) and mitochondrial dysfunction [54]. Alterations in ψm induce the process of mitochondrial dynamics as a repair response to possible damage to this organelle. Mitochondrial dynamics depends on two mechanisms: fission and fusion; the first one is caused by various types of stress and requires protein activity such as Drp-1, on the other hand, fusion requires the recovery of ψm and proteins such as mitofusin 1 and 2 (MFN 1 and 2) [44]. Mitochondrial fusion promotes cristae formation and normal mitochondria phenotype [55]. Morphological alterations in mitochondria determined through electronic microscopy in various models of hepatic fibrosis have been described a long time ago [56, 57].

Previously, it has been discussed some of the effects of adenosine (base molecule of IFC-305), which include increase in energy parameters and regulation of the redox state. Considering this background and what has been described regarding the metabolic and mitochondrial changes in chronic liver damage, such as cirrhosis and HCC, it was decided to evaluate whether IFC-305 had any mitochondrial effect in the sequential model of cirrhosis-HCC.

In the sequential model of cirrhosis-HCC, decreased mitochondrial respiration, determined through oxygen consumption, and a decreased ψm were found, which reflected in a diminished ATP synthesis. In fact, the dimeric form (active form) of the F1F0 complex of ATPase is lost [43].

On the other hand, alterations in the mitochondrial redox state were observed, determined through the ratio of the levels of β-hydroxybutyrate/acetoacetate (NAD+/NADH). The activity of NAD-dependent enzymes was also affected, such is the case of IDH and PARP-1; this alteration induced a metabolic adaptation because increased levels of lactate were observed suggesting an increase in aerobic glycolysis [43].

It is known that the mitochondrion is capable of responding to several insults of stress through the activity of various nuclear-encoded proteins like PGC-1α and Sirt-1. However, the over-regulation of these proteins has been associated with the accumulation of dysfunctional mitochondria, as described above. In the model previously described, these proteins were found increased. Dysfunctional mitochondria have been related to their morphology, and we know that morphology is closely linked to dynamism. The ratio of Drp-1/MFN-2, proteins that regulate the mitochondrial dynamics, was increased favoring the fragmented form of mitochondria as verified through electron microscopy [43].

Important findings were observed with the IFC-305 treatment as described in Table 1 [43].

Mitochondrial parameterEffect
FunctionMaintained and recovered:
  • mitochondrial respiration

  • ATP synthesis

  • mitochondrial membrane potential

  • dimeric form of the F1F0 ATPase subunit

  • normal cellular redox state

  • Recovered the normal mitochondrial redox state

  • recovered the IDH activity

  • reduced lactate production

  • diminished increased PARP-1 activity

DynamicsAvoided the accumulation of dysfunctional mitochondria through:
  • down-regulation of PGC-1α and Sirt-1

  • diminution of DRP-1/MFN-2 ratio

  • Sirt-3 increment

Table 1.

Effects of IFC-305 administration in mitochondria in the sequential model of cirrhosis-HCC.

Uncoupled mitochondria depicted lower ATP synthesis due to the altered ψm and complex I activity. Previously, it has been demonstrated that complex I is sensitive to DEN toxicity, as NAD+ linked respiration is inhibited [58]. Recovery of these parameters with IFC-305 treatment was observed, including the activity of NAD+-dependent IDH. The PARP-1 activity inhibition probably favored the NAD+ availability and contributed to the maintenance of the redox state. Mitochondrial function preservation and restoration allowed the normalization of the metabolism observed by lactate levels diminution.

On the other hand, the decreased Sirt-1 and PGC-1α in the groups treated with IFC-305 suggested that abnormal mitochondrial accumulation was inhibited. In fact, mitochondrial dynamics regulation was induced by IFC-305. These results demonstrated mitochondrial impairment through functional, metabolic, and dynamic alterations in HCC, and the hepatoprotector IFC-305 helps to repair them, being a tumor suppressive mechanism.

These findings support the mitochondrial role in the establishment of HCC and the interplay with the nuclear genome as targets in the design of new therapeutic strategies for the HCC treatment. In this regard, the IFC-305 supports that idea and emerges as a new possible HCC therapy through mitochondrial regulation.

According to the above, there is a growing interest to find pharmacological strategies to block the effects of mitochondrial dysfunction in HCC. Regarding this, in the model of HCC induced with DEN, a study was conducted to determine the mitochondrial effects of ginkgolide B in two different pharmaceutical formulations, finding a decrease in the mitochondrial generation of ROS and a decrease in the dissipation of the mitochondrial membrane potential [59]. Moreover, two of the most studied hepatoprotective compounds until now are resveratrol and N-acetylcysteine (NAC) [60]. On the one hand, resveratrol inhibits the formation of hepatocyte nodules in the DEN-induced HCC model plus phenobarbital administration; moreover, it is capable of modulating mitochondrial biogenesis [61]. On the other hand, NAC blocked phosphorylation of β-catenin, JNK, and c-jun activation, avoiding the development of liver damage in HCC transaldolase-deficient mice, a limiting enzyme for the non-oxidative branch of the pentose phosphate pathway, which is, at least in part, responsible for HCC generation [62]; furthermore, NAC stabilizes the mitochondrial membrane potential regulating mitochondrial dynamics [61].


4. Interaction of mitochondria and epigenetics in HCC: An overview

The epigenome can be altered not only by environmental factors, such as exposure to exogenous chemicals [63] but also by changes in the levels of endogenous cofactors and metabolites [64, 65]. The exact correlation between nucleus and mitochondrion allows for the maintenance of mitochondrial structure and function. On the one hand, the nuclear gene expression is regulated by mitochondrial intermediates, like acetyl-CoA, ATP, NAD+, and s-adenosylmethionine, which are the link between the epigenome and calorie availability [47, 66]. In addition to the production of epigenetic substrates, mitochondria may be modified in their DNA (mtDNA). Some mitochondrial genes have been reported as hypermethylated in HCC; for example, mitochondrial ribosomal protein S12 (Mrps12), mitochondria-localized glutamic acid-rich protein (Mgrap), and transmembrane protein 70 (Tmem70) genes [67, 68]. On the other hand, the disruption of the step in the methylation of 5-mC to 5-hmC in the mitochondrial genome leads to the alteration of several OXPHOS genes, such as: NADH dehydrogenase (ubiquinone) 1 subunit C2 (NDUFC2), NADH dehydrogenase (ubiquinone) flavoprotein 1 (NDUFV1), NADH: ubiquinone oxidoreductase subunit S6 (NDUFS6) from complex 1. These modifications, added to the mitochondrial damage by oxidative stress, can favor the loss of ETC function. In addition to that, it has been reported that the mitochondrial genome damage can affect the expression of nuclear genes [69, 70, 71]. Moreover, there is a deregulation of hepatic one carbon, and TCA cycle, therefore it driving the aberrant epigenetics changes [72, 73, 74]. The main consequence of depressing the TCA cycle is the reduced availability of α-ketoglutarate, leading to a decrease in the activity of α-ketoglutarate-dependent proteins, which are responsible for the hydroxylation of many substrates in the cell that are important in epigenomic control [74].

Tumor cell metabolism can be linked to epigenetic changes during carcinogenesis; recent research has focused on epigenetic studies in relation to metabolic pathways [75, 76]. HCC is a heterogeneous disease affected by various lifestyles and environmental factors. Epigenetic alterations are frequently caused by these factors and contribute to hepatocarcinogenesis. During HCC development, different alterations in global DNA methylation have been described; for example, global hypomethylation leads to aberrant overexpression of oncogenes and large chromosomal instability [77, 78].

In cirrhosis and HCC, distinct patterns of aberrant DNA methylation associated with cirrhosis and HCC have been confirmed [79, 80].


5. Conclusion

The pathophysiology of HCC is multifactorial and involves mitochondrial dysfunction. Mitochondria usually generate relevant modulators of gene expression controlled by epigenetic mechanisms. These alterations induce chromosomic instability that could give advantages to subclones of cells to their outgrowth (Figure 1). Further studies are needed to find therapeutic strategies capable of maintaining and improving the mitochondrial integrity to avoid alterations in the epigenetic regulation of nuclear- and mitochondrial-encoded genes. These effects could suppress failures in cell cycle checkpoints and the uncontrolled proliferation to prevent or reverse HCC as demonstrated for IFC-305.

Figure 1.

(A) In the model of liver injury induced by diethylnitrosamine (DEN), the architecture of the liver parenchyma is altered causing an exacerbated proliferation of various transformed clones, where the presence of a large number of tumors randomly distributed in each one is observed in the hepatic lobules. The preneoplastic nodules that form are surrounded by septa of collagen fibers; thus, favoring the evasion of the immune system and an ideal hypoxic microenvironment for the tumor cells. The genomic instability caused by the toxic as well as favoring mutations, for example in p53, and various alterations in different cellular modulators, among them HGF, c-Met, PCNA, gankyrin and p27. It also causes an increase of proteins, deacetylating PGC1-α, and, thus, modifies various nuclear genes exported to the mitochondria, causing accumulation of abnormal and dysfunctional mitochondria. (B) In the model of hepatocarcinoma induced by DEN, the administration of the adenosine derivative, IFC-305, has been shown to have various regulatory effects. The excessive accumulation of collagen fibers in preneoplastic nodules as well as the number and size of tumors are reduced. Also, cell morphology and DNA recover significantly. A decrease in the deacetylase Sirt-1, whose target is PCG1-α, has been observed, which allows the latter to remain acetylated and can be internalized to mitochondria, where it will promote its adequate morphology, dynamics and function. It has also been found that the compound IFC-305 acts on the levels of some important modulators in cancer (p53, HGF, C-Met…), maintaining or returning them to their concentrations under normal conditions. Overall, the aforementioned effects make this compound a possible therapeutic alternative.



This work was supported by Consejo Nacional de Ciencia y Tecnología (240315) and DGAPA-UNAM, grant numbers IN208915 VCS.


Conflict of interest

The author(s) declared no potential conflicts of interest respect to the research, authorship, and/or publication of this chapter.



HCChepatocellular carcinoma
PARP-1poly (ADP-ribose) polymerase-1
TACEtranscatheter arterial chemoembolization
HSChepatic stellate cells
ECMextracellular matrix
HGFhepatocyte growth factor
IGRinsulin growth factor
TGF-βtransforming growth factor-β
NAD+nicotinamide adenine dinucleotide oxidized
NADHnicotinamide adenine dinucleotide reduced
CCl4carbon tetrachloride
VEGFVascular Endothelial Growth Factor
OXPHOSoxidative phosphorylation
SCO2chaperone protein “synthesis of cytochrome c oxidase 2”
ROSreactive oxygen species
TIGARTP53-induced glycolysis and apoptosis regulator
PCNAproliferating cell nuclear antigen
GSHglutathione reduced
TCAtricarboxylic acids chain
ETCelectron transport chain
IDHisocitrate dehydrogenase
PGC-1αperoxisome proliferator-activated receptor gamma coactivator 1-alpha
ψmmitochondrial membrane potential
MFN 1mitofusin 1
MFN 2mitofusin 2
mtDNAmitochondrial DNA
Mrps12mitochondrial ribosomal protein S12 gene
Mgrapmitochondria-localized glutamic acid-rich protein gene
Tmem70transmembrane protein 70 gene
NDUFC2NADH dehydrogenase (ubiquinone) 1 subunit C2
NDUFV1NADH dehydrogenase (ubiquinone) flavoprotein 1
NDUFS6NADH: ubiquinone oxidoreductase subunit S6


  1. 1. Sanyal AJ, Yoon SK, Lencioni R. The etiology of hepatocellular carcinoma and consequences for treatment. The Oncologist. 2010;15(Suppl 4):14-22. DOI: 10.1634/theoncologist.2010-S4-14
  2. 2. Cucchetti A, Piscaglia F, Cescon M, Ercolani G, Terzi E, Bolondi L, Zanello M, Pinna AD. Conditional survival after hepatic resection for hepatocellular carcinoma in cirrhotic patients. Clinical Cancer Research. 2012;18(16):4397-4405. DOI: 10.1158/1078-0432.CCR-11-2663
  3. 3. Erstad DJ, Fuchs BC, Tanabe KK. Molecular signatures in hepatocellular carcinoma: A step toward rationally designed cancer therapy. Cancer. 2018. DOI: 10.1002/cncr.31257
  4. 4. Sanoff HK, Chang Y, Lund JL, O'Neil BH, Dusetzina SB. Sorafenib effectiveness in advanced hepatocellular carcinoma. The Oncologist. 2016;21(9):1113-1120. DOI: 10.1634/theoncologist.2015-0478
  5. 5. Rappaport A. Physioanatomic considerations. In: Schiff L, Schiff ER, editors. Diseases of the Liver. Philadelphia: Lippincott Company; 1987. pp. 1-46
  6. 6. Tygstrup N, Winkler K, Mellemgaard K, Andreassen M. Determination of the hepatic arterial blood flow and oxygen supply in man by clamping the hepatic artery during surgery. The Journal of Clinical Investigation. 1962;41:447-454. DOI: 10.1172/JCI104497
  7. 7. Jones AL, Hradek GT, Renston RH, Wong KY, Karlaganis G, Paumgartner G. Autoradiographic evidence for hepatic lobular concentration gradient of bile acid derivative. The American Journal of Physiology. 1980;238(3):G233-G237. DOI: 10.1152/ajpgi.1980.238.3.G233
  8. 8. Zucker SG, Brown JL. Physiology of the liver. In: Fenton Schaffner HB, Edward Berk J, editors. Bockus Gastroenterology. Philadelphia, Pennsylvania: Saunders Company; 1995. pp. 1858-1905
  9. 9. Laskin DL. Nonparenchymal cells and hepatotoxicity. Seminars in Liver Disease. 1990;10(4):293-304. DOI: 10.1055/s-2008-1040485
  10. 10. Kaneda K, Wake K. Distribution and morphological characteristics of the pit cells in the liver of the rat. Cell and Tissue Research. 1983;233(3):485-505
  11. 11. Ramadori G, Rieder H, Knittel T. Hepatic transport and bile secretion: Physiology and pathophysiology. In: Tavolini N, Berk PD, editors. Biology and Pathobiology of Sinusoidal Liver Cells. New York: Raven Press; 1993. pp. 83-102
  12. 12. Chojkier M, Lyche KD, Filip M. Increased production of collagen in vivo by hepatocytes and nonparenchymal cells in rats with carbon tetrachloride-induced hepatic fibrosis. Hepatology. 1988;8(4):808-814
  13. 13. Chagoya V. Interrelaciones metabolicas entre tejidos. Adaptación metabólica al ayuno y al ejercicio. In: Castillón E, editor. Bioquímica. España: EMALSA, S.A; 1986. pp. 1183-1194
  14. 14. Chagoya de Sanchez V, Brunner A, Pina E. In vivo modification of the energy charge in the liver cell. Biochemical and Biophysical Research Communications. 1972;46(3):1441-1445
  15. 15. De Sanchez VC, Pina E. Adenosine, a glucogenic and lipogenic compound. FEBS Letters. 1972;19(4):331-334
  16. 16. Chagoya de Sanchez V, Hernandez-Munoz R, Sanchez L, Vidrio S, Yanez L, Suarez J. Twenty-four-hour changes of S-adenosylmethionine, S-adenosylhomocysteine adenosine and their metabolizing enzymes in rat liver; possible physiological significance in phospholipid methylation. The International Journal of Biochemistry. 1991;23(12):1439-1443
  17. 17. De Sanchez VC, Piña E. The redox state of NAD+/NADH systems in rat liver during in vivo inhibition of fatty acid oxidation by adenosine. FEBS Letters. 1977;83(2):321-324
  18. 18. Chagoya de Sánchez V, Piña E. Support for energy-charge model. Trends in Biochemical Sciences. 1978;3:N14-N15
  19. 19. Hohorst HJ, Kreutz FH, Reim M, Huebener HJ. The oxidation/reduction state of the extramitochondrial DPN/DPNH system in rat liver and the hormonal control of substrate levels in vivo. Biochemical and Biophysical Research Communications. 1961;4:163-168
  20. 20. Lautt WW. Mechanism and role of intrinsic regulation of hepatic arterial blood flow: Hepatic arterial buffer response. The American Journal of Physiology. 1985;249(5 Pt 1):G549-G556
  21. 21. Hernandez-Munoz R, Santamaria A, Garcia-Sainz JA, Pina E, Chagoya de Sanchez V. On the mechanism of ethanol-induced fatty liver and its reversibility by adenosine. Archives of Biochemistry and Biophysics. 1978;190(1):155-162
  22. 22. Garcia-Sainz JA, Hernandez-Munoz R, Santamaria A, de Sanchez VC. Mechanism of the fatty liver induced by cycloheximide and its reversibility by adenosine. Biochemical Pharmacology. 1979;28(8):1409-1413
  23. 23. Hernandez-Munoz R, Glender W, Diaz Munoz M, Adolfo J, Garcia-Sainz JA, Chagoya de Sanchez V. Effects of adenosine on liver cell damage induced by carbon tetrachloride. Biochemical Pharmacology. 1984;33(16):2599-2604
  24. 24. Friedman SL. Mechanisms of hepatic fibrogenesis. Gastroenterology. 2008;134(6):1655-1669. DOI: 10.1053/j.gastro.2008.03.003
  25. 25. Perez Tamayo R. Is cirrhosis of the liver experimentally produced by CCl4 and adequate model of human cirrhosis? Hepatology. 1983;3(1):112-120
  26. 26. Hernandez-Munoz R, Diaz-Munoz M, Suarez J, Chagoya de Sanchez V. Adenosine partially prevents cirrhosis induced by carbon tetrachloride in rats. Hepatology. 1990;12(2):242-248
  27. 27. Hernandez-Munoz R, Diaz-Munoz M, Suarez-Cuenca JA, Trejo-Solis C, Lopez V, Sanchez-Sevilla L, Yanez L, De Sanchez VC. Adenosine reverses a preestablished CCl4-induced micronodular cirrhosis through enhancing collagenolytic activity and stimulating hepatocyte cell proliferation in rats. Hepatology. 2001;34(4 Pt 1):677-687. DOI: 10.1053/jhep.2001.27949
  28. 28. Chagoya de Sánchez V, Hernandez-Luis F, Díaz-Muñoz M, Hernández-Muñoz R. Role of the energy state of liver cells in cirrhosis development and treatment. In: Michelli ML, editor. Liver Cirrhosis: Causes, Diagnosisand Treatment. Nova Science Publisher; 2011. pp. 31-59
  29. 29. Perez-Carreon JI, Martinez-Perez L, Loredo ML, Yanez-Maldonado L, Velasco-Loyden G, Vidrio-Gomez S, Ramirez-Salcedo J, Hernandez-Luis F, Velazquez-Martinez I, Suarez-Cuenca JA, Hernandez-Munoz R, de Sanchez VC. An adenosine derivative compound, IFC305, reverses fibrosis and alters gene expression in a pre-established CCl(4)-induced rat cirrhosis. The International Journal of Biochemistry & Cell Biology. 2010;42(2):287-296. DOI: 10.1016/j.biocel.2009.11.005
  30. 30. Rodriguez-Aguilera JR, Guerrero-Hernandez C, Perez-Molina R, Cadena-Del-Castillo CE, de Vaca RP, Guerrero-Celis N, Dominguez-Lopez M, Murillo-de-Ozores AR, Arzate-Mejia R, Recillas-Targa F, de Sanchez VC. Epigenetic effects of an adenosine derivative in a Wistar rat model of liver cirrhosis. Journal of Cellular Biochemistry. 2018. DOI: 10.1002/jcb.26192
  31. 31. Pérez-Cabeza de Vaca R, Domínguez-López M, Guerrero-Celis N, Rodríguez-Aguilera JR, Chagoya de Sánchez V. Inflammation is regulated by the adenosine derivative molecule IFC-305, during reversion of cirrhosis in a CCl4 rat model. International Immunopharmacology. 2018;54:12-23
  32. 32. Delgado-Coello B, Briones-Orta MA, Macias-Silva M, Mas-Oliva J. Cholesterol: Recapitulation of its active role during liver regeneration. Liver International. 2011;31(9):1271-1284. DOI: 10.1111/j.1478-3231.2011.02542.x
  33. 33. Wallace MC, Friedman SL. Hepatic fibrosis and the microenvironment: Fertile soil for hepatocellular carcinoma development. Gene Expression. 2014;16(2):77-84. DOI: 10.3727/105221614X13919976902057
  34. 34. El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 2007;132(7):2557-2576. DOI: 10.1053/j.gastro.2007.04.061
  35. 35. Jin Y, Ding K, Wang D, Shen M, Pan J. Novel thiazole amine class tyrosine kinase inhibitors induce apoptosis in human mast cells expressing D816V KIT mutation. Cancer Letters. 2014;353(1):115-123. DOI: 10.1016/j.canlet.2014.07.017
  36. 36. Shiraha H, Yamamoto K, Namba M. Human hepatocyte carcinogenesis (review). International Journal of Oncology. 2013;42(4):1133-1138. DOI: 10.3892/ijo.2013.1829
  37. 37. Wallace DC. Mitochondria and cancer. Nature Reviews. Cancer. 2012;12(10):685-698. DOI: 10.1038/nrc3365
  38. 38. Chagoya de Sanchez V, Martinez-Perez L, Hernandez-Munoz R, Velasco-Loyden G. Recovery of the cell cycle inhibition in CCl(4)-induced cirrhosis by the adenosine derivative IFC-305. International Journal of Hepatology. 2012;2012:212530. DOI: 10.1155/2012/212530
  39. 39. Velasco-Loyden G, Perez-Martinez L, Vidrio-Gomez S, Perez-Carreon JI, Chagoya de Sanchez V. Cancer chemoprevention by an adenosine derivative in a model of cirrhosis-hepatocellular carcinoma induced by diethylnitrosamine in rats. Tumour Biology. 2017;39(2):1010428317691190. DOI: 10.1177/1010428317691190
  40. 40. Nakamura T, Sakai K, Matsumoto K. Hepatocyte growth factor twenty years on: Much more than a growth factor. Journal of Gastroenterology and Hepatology. 2011;26(Suppl 1):188-202. DOI: 10.1111/j.1440-1746.2010.06549.x
  41. 41. Gómez-Quiroz LE, Gutiérrez-Ruiz MC, Marquardt JU, Factor VM, Thorgeirsson SS. Redox regulation by HGF/c-Met in liver disease. In: Muriel P, editor. Liver Pathophysiology: Therapies and Antioxidants. 2017. pp. 375-387
  42. 42. Miura D, Miura Y, Yagasaki K. Resveratrol inhibits hepatoma cell invasion by suppressing gene expression of hepatocyte growth factor via its reactive oxygen species-scavenging property. Clinical & Experimental Metastasis. 2004;21(5):445-451
  43. 43. Chavez E, Lozano-Rosas MG, Dominguez-Lopez M, Velasco-Loyden G, Rodriguez-Aguilera JR, Jose-Nunez C, Tuena de Gomez-Puyou M, Chagoya de Sanchez V. Functio-nal, metabolic, and dynamic mitochondrial changes in the rat cirrhosis-hepatocellular carcinoma model and the protective effect of IFC-305. The Journal of Pharmacology and Experimental Therapeutics. 2017;361(2):292-302. DOI: 10.1124/jpet.116.239301
  44. 44. Boland ML, Chourasia AH, Macleod KF. Mitochondrial dysfunction in cancer. Frontiers in Oncology. 2013;(3). DOI: 292. 10.3389/fonc.2013.00292
  45. 45. Eltzschig HK, Carmeliet P. Hypoxia and inflammation. The New England Journal of Medicine. 2011;364(7):656-665. DOI: 10.1056/NEJMra0910283
  46. 46. Hernandez-Munoz R, Glender W, Diaz-Munoz M, Suarez J, Lozano J, Chagoya de Sanchez V. Alterations of ATP levels and of energy parameters in the blood of alcoholic and nonalcoholic patients with liver damage. Alcoholism, Clinical and Experimental Research. 1991;15(3):500-503
  47. 47. Wallace DC, Fan W. Energetics, epigenetics, mitochondrial genetics. Mitochondrion. 2010;10(1):12-31. DOI: 10.1016/j.mito.2009.09.006
  48. 48. Hsu CC, Lee HC, Wei YH. Mitochondrial DNA alterations and mitochondrial dysfunction in the progression of hepatocellular carcinoma. World Journal of Gastroenterology. 2013;19(47):8880-8886. DOI: 10.3748/wjg.v19.i47.8880
  49. 49. Pietrocola F, Galluzzi L, Bravo-San Pedro JM, Madeo F, Kroemer G. Acetyl coenzyme a: A central metabolite and second messenger. Cell Metabolism. 2015;21(6):805-821. DOI: 10.1016/j.cmet.2015.05.014
  50. 50. Hernandez-Munoz R, Diaz-Munoz M, Chagoya de Sanchez V. Effects of adenosine administration on the function and membrane composition of liver mitochondria in carbon tetrachloride-induced cirrhosis. Archives of Biochemistry and Biophysics. 1992;294(1):160-167
  51. 51. Nishikawa T, Bellance N, Damm A, Bing H, Zhu Z, Handa K, Yovchev MI, Sehgal V, Moss TJ, Oertel M, Ram PT, Pipinos II, Soto-Gutierrez A, Fox IJ, Nagrath D. A switch in the source of ATP production and a loss in capacity to perform glycolysis are hallmarks of hepatocyte failure in advance liver disease. Journal of Hepatology. 2014;60(6):1203-1211. DOI: 10.1016/j.jhep.2014.02.014
  52. 52. Dang L, Yen K, Attar EC. IDH mutations in cancer and progress toward development of targeted therapeutics. Annals of Oncology. 2016;27(4):599-608. DOI: 10.1093/annonc/mdw013
  53. 53. Hanahan D, Weinberg RA. Hallmarks of cancer: The next generation. Cell. 2011;144(5):646-674. DOI: 10.1016/j.cell.2011.02.013
  54. 54. Morales J, Li L, Fattah FJ, Dong Y, Bey EA, Patel M, Gao J, Boothman DA. Review of poly (ADP-ribose) polymerase (PARP) mechanisms of action and rationale for targeting in cancer and other diseases. Critical Reviews in Eukaryotic Gene Expression. 2014;24(1):15-28
  55. 55. Liesa M, Borda-d'Agua B, Medina-Gomez G, Lelliott CJ, Paz JC, Rojo M, Palacin M, Vidal-Puig A, Zorzano A. Mitochondrial fusion is increased by the nuclear coactivator PGC-1beta. PLoS One. 2008;3(10):e3613. DOI: 10.1371/journal.pone.0003613
  56. 56. Moller B, Dargel R. Structural and functional impairment of mitochondria from rat livers chronically injured by thioacetamide. Acta Pharmacologica et Toxicologica (Copenh). 1984;55(2):126-132
  57. 57. Jezequel AM, Mancini R, Rinaldesi ML, Macarri G, Venturini C, Orlandi F. A morphological study of the early stages of hepatic fibrosis induced by low doses of dimethylnitrosamine in the rat. Journal of Hepatology. 1987;5(2):174-181
  58. 58. Boitier E, Merad-Boudia M, Guguen-Guillouzo C, Defer N, Ceballos-Picot I, Leroux JP, Marsac C. Impairment of the mitochondrial respiratory chain activity in diethylnitrosamine-induced rat hepatomas: Possible involvement of oxygen free radicals. Cancer Research. 1995;55(14):3028-3035
  59. 59. Ghosh S, Dungdung SR, Choudhury ST, Chakraborty S, Das N. Mitochondria protection with ginkgolide B-loaded polymeric nanocapsules prevents diethylnitrosamine-induced hepatocarcinoma in rats. Nanomedicine (London, England). 2014;9(3):441-456. DOI: 10.2217/nnm.13.56
  60. 60. Chavez E, Reyes-Gordillo K, Segovia J, Shibayama M, Tsutsumi V, Vergara P, Moreno MG, Muriel P. Resveratrol prevents fibrosis, NF-kappaB activation and TGF-beta increases induced by chronic CCl4 treatment in rats. Journal of Applied Toxicology. 2008;28(1):35-43. DOI: 10.1002/jat.1249
  61. 61. Chávez E, Galicia M, Muriel P. Are N-acetylcysteine and resveratrol effective treatments for liver disease? In: Muriel P, editor. Liver Pathophysiology: Therapies and Antioxidants. London, United Kingdom: Academic Press, Elsevier; 2017. pp. 729-742
  62. 62. Perl A, Hanczko R, Telarico T, Oaks Z, Landas S. Oxidative stress, inflammation and carcinogenesis are controlled through the pentose phosphate pathway by transaldolase. Trends in Molecular Medicine. 2011;17(7):395-403. DOI: 10.1016/j.molmed.2011.01.014
  63. 63. Baccarelli A, Bollati V. Epigenetics and environmental chemicals. Current Opinion in Pediatrics. 2009;21(2):243-251
  64. 64. Herceg Z, Vaissiere T. Epigenetic mechanisms and cancer: An interface between the environment and the genome. Epigenetics. 2011;6(7):804-819. DOI: 10.4161/epi.6.7.16262
  65. 65. Turner BM. Epigenetic responses to environmental change and their evolutionary implications. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 2009;364(1534):3403-3418. DOI: 10.1098/rstb.2009.0125
  66. 66. Lozano-Rosas MG, Chávez E, Aparicio-Cadena AR, Velasco-Loyden G, Chagoya de Sánchez V. Mitoepigenetics and hepatocellular carcinoma. Hepatoma Research. 2018;4:1-14. DOI: 10.20517/2394-5079.2018.48
  67. 67. Shock LS, Thakkar PV, Peterson EJ, Moran RG, Taylor SM. DNA methyltransferase 1, cytosine methylation, and cytosine hydroxymethylation in mammalian mitochondria. Proceedings of the National Academy of Sciences of the United States of America. 2011;108(9):3630-3635. DOI: 10.1073/pnas.1012311108
  68. 68. Mizukami S, Yafune A, Watanabe Y, Nakajima K, Jin M, Yoshida T, Shibutani M. Identification of epigenetically downregulated Tmem70 and Ube2e2 in rat liver after 28-day treatment with hepatocarcinogenic thioacetamide showing gene product downregulation in hepatocellular preneoplastic and neoplastic lesions produced by tumor promotion. Toxicology Letters. 2017;266:13-22. DOI: 10.1016/j.toxlet.2016.11.022
  69. 69. Malik AN, Czajka A. Is mitochondrial DNA content a potential biomarker of mitochondrial dysfunction? Mitochondrion. 2013;13(5):481-492. DOI: 10.1016/j.mito.2012.10.011
  70. 70. Singh KK, Kulawiec M, Still I, Desouki MM, Geradts J, Matsui S. Inter-genomic cross talk between mitochondria and the nucleus plays an important role in tumorigenesis. Gene. 2005;354:140-146. DOI: 10.1016/j.gene.2005.03.027
  71. 71. Ye C, Tao R, Cao Q, Zhu D, Wang Y, Wang J, Lu J, Chen E, Li L. Whole-genome DNA methylation and hydroxymethylation profiling for HBV-related hepatocellular carcinoma. International Journal of Oncology. 2016;49(2):589-602. DOI: 10.3892/ijo.2016.3535
  72. 72. Maier K, Hofmann U, Reuss M, Mauch K. Dynamics and control of the central carbon metabolism in hepatoma cells. BMC Systems Biology. 2010;4:54. DOI: 10.1186/1752-0509-4-54
  73. 73. Stubbs M, Griffiths JR. The altered metabolism of tumors: HIF-1 and its role in the Warburg effect. Advances in Enzyme Regulation. 2010;50(1):44-55. DOI: 10.1016/j.advenzreg.2009.10.027
  74. 74. Puszyk WM, Trinh TL, Chapple SJ, Liu C. Linking metabolism and epigenetic regulation in development of hepatocellular carcinoma. Laboratory Investigation. 2013;93(9):983-990. DOI: 10.1038/labinvest.2013.94
  75. 75. Cyr AR, Domann FE. The redox basis of epigenetic modifications: From mechanisms to functional consequences. Antioxidants & Redox Signaling. 2011;15(2):551-589. DOI: 10.1089/ars.2010.3492
  76. 76. Shyh-Chang N, Locasale JW, Lyssiotis CA, Zheng Y, Teo RY, Ratanasirintrawoot S, Zhang J, Onder T, Unternaehrer JJ, Zhu H, Asara JM, Daley GQ, Cantley LC. Influence of threonine metabolism on S-adenosylmethionine and histone methylation. Science. 2013;339(6116):222-226. DOI: 10.1126/science.1226603
  77. 77. Herath NI, Leggett BA, MacDonald GA. Review of genetic and epigenetic alterations in hepatocarcinogenesis. Journal of Gastroenterology and Hepatology. 2006;21(1 Pt 1):15-21. DOI: 10.1111/j.1440-1746.2005.04043.x
  78. 78. Calvisi DF, Ladu S, Gorden A, Farina M, Lee JS, Conner EA, Schroeder I, Factor VM, Thorgeirsson SS. Mechanistic and prognostic significance of aberrant methylation in the molecular pathogenesis of human hepatocellular carcinoma. The Journal of Clinical Investigation. 2007;117(9):2713-2722. DOI: 10.1172/JCI31457
  79. 79. Shen J, Wang S, Zhang YJ, Kappil M, Wu HC, Kibriya MG, Wang Q, Jasmine F, Ahsan H, Lee PH, Yu MW, Chen CJ, Santella RM. Genome-wide DNA methylation profiles in hepatocellular carcinoma. Hepatology. 2012;55(6):1799-1808. DOI: 10.1002/hep.25569
  80. 80. Nishida N, Kudo M, Nagasaka T, Ikai I, Goel A. Characteristic patterns of altered DNA methylation predict emergence of human hepatocellular carcinoma. Hepatology. 2012;56(3):994-1003. DOI: 10.1002/hep.25706

Written By

Victoria Chagoya de Sánchez, Enrique Chávez, Gabriela Velasco- Loyden, María Guadalupe Lozano-Rosas and Alejandro Rusbel Aparicio-Cadena

Submitted: April 6th, 2018 Reviewed: July 3rd, 2018 Published: November 5th, 2018