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inflammation is the translocation of intestinal bacteria from the gut.TLR4 and intestinal microbiota has
been implicated in HCC progression and are suggested as potential new targets for chemoprevention
[6].There is evidence of a deleterious effect of gut microbiome in HSC function. In fibrotic livers, HSC
are immunologically active and release mediators that promote progression from NAFLD to HCC,
a phenotype related to impaired senescence. IL6 and de-regulated STAT3 signalling have also been
implicated in inflammation-related HCC. In terms of inflammatory mediators of NASH-related HCC,
a recent report underscored the role of intrahepatic activation of CD8+ T and NK cells to promote
oncogenesis in a model of high-fat diet induced HCC. More recently, an animal model of ER stress
points towards a central role of TNFα in tumor progression in NAFLD/NASH-HCC.
2. Metabolism and autophagy: Hyperinsulinemia is a frequent finding in patients with NAFLD/
NASH and, as mentioned above, there are strong epidemiological links between T2DM and HCC.
Insulin has a pivotal role in cell metabolism and it exerts its metabolic effects via the PI3K/AKT/mTOR
pathway among others. PI3K signalling is inhibited by PTEN, which has been consistently reported as
a tumor suppressor gene in human cancer. In HCC, close to 50% of cases have PTEN loss, but not
due to inactivating mutations as is the case in other solid tumors. Data from animal models implicates
PTEN loss in NASH and HCC. Similarly, PI3K transgenic mice also develop HCC in the context of
NASH. AKT was also found activated in PDGFR transgenic mice, which developed HCC and NASH
in the absence of significant fibrosis.
The peroxisome proliferation-activated receptors (PPARs) have also been implicated in the pathogenesis
of NAFLD/NASH-HCC [7]. PPARs are a family of ligand-activated transcription factors with a central
role in regulation of glucose and lipid homeostasis. They participate in inflammation, cell survival and
differentiation through release of HDAC co-repressors. In mice, chronic exposure to PPARα agonists
induces liver tumors via let-7. This miRNA is significantly repressed in HCC and modulates MYC
expression. There are also experimental links between decrease activity of the farsenoid X receptor
(FXR) and HCC [8]. FXR is a transcription factor that participates in metabolic homeostasis and
inflammation, and there is data showing decreased FXR expression in NAFLD patients. Interestingly,
liver tumors in FXR deficient mice show aberrant WNT signaling in the context of chronic liver
inflammation and fibrosis.
Autophagy has also emerged as an important cellular module in carcinogenesis. It is involved in the
elimination of damaged cellular components through lysosomal degradation and it is capable of
inducing programmed cell death. There is evidence that links global inhibition of autophagy in the
liver to steatosis, which is supported by data on impaired autophagy in experimental models of HCC.
Theoretically, restoration of autophagy could be beneficial to counteract the pro-tumorigenic effects of
NASH [9].
3. Oxidative stress: Fat accumulation in hepatocytes induces the generation of ROS that can interfere
with mitochondrial function, induce ER stress and generate genotoxins such as lipid peroxides.
Damaged DNA within hepatocytes is a potential trigger of malignant transformation and the expansion
of the progenitor cell compartment. Numerous studies implicate methionine metabolism and
s-adenosylmethionine (SAM) in HCC development [10]. MAT1A-deficient mice develop progressive
NAFLD and HCC. These mice have a marked reduction in SAM levels and increased lipid peroxides
in the serum, consistent with increased oxidative stress. Interestingly, GNMT knockout mice exhibit
high levels of hepatic SAM, and they also develop NAFLD and HCC. In this case, it seems that SAM-
induced epigenetic disarray due to aberrant DNA methylation may significantly contribute to malignant
transformation. A combination of global DNA hypomethylation in addition to generation of ROS and
nitro-active species justify these pleiotropic effects reported for hepatic SAM levels.
The International Liver Congress™ 2015 • Vienna, Austria • April 22–23, 2015 79
been implicated in HCC progression and are suggested as potential new targets for chemoprevention
[6].There is evidence of a deleterious effect of gut microbiome in HSC function. In fibrotic livers, HSC
are immunologically active and release mediators that promote progression from NAFLD to HCC,
a phenotype related to impaired senescence. IL6 and de-regulated STAT3 signalling have also been
implicated in inflammation-related HCC. In terms of inflammatory mediators of NASH-related HCC,
a recent report underscored the role of intrahepatic activation of CD8+ T and NK cells to promote
oncogenesis in a model of high-fat diet induced HCC. More recently, an animal model of ER stress
points towards a central role of TNFα in tumor progression in NAFLD/NASH-HCC.
2. Metabolism and autophagy: Hyperinsulinemia is a frequent finding in patients with NAFLD/
NASH and, as mentioned above, there are strong epidemiological links between T2DM and HCC.
Insulin has a pivotal role in cell metabolism and it exerts its metabolic effects via the PI3K/AKT/mTOR
pathway among others. PI3K signalling is inhibited by PTEN, which has been consistently reported as
a tumor suppressor gene in human cancer. In HCC, close to 50% of cases have PTEN loss, but not
due to inactivating mutations as is the case in other solid tumors. Data from animal models implicates
PTEN loss in NASH and HCC. Similarly, PI3K transgenic mice also develop HCC in the context of
NASH. AKT was also found activated in PDGFR transgenic mice, which developed HCC and NASH
in the absence of significant fibrosis.
The peroxisome proliferation-activated receptors (PPARs) have also been implicated in the pathogenesis
of NAFLD/NASH-HCC [7]. PPARs are a family of ligand-activated transcription factors with a central
role in regulation of glucose and lipid homeostasis. They participate in inflammation, cell survival and
differentiation through release of HDAC co-repressors. In mice, chronic exposure to PPARα agonists
induces liver tumors via let-7. This miRNA is significantly repressed in HCC and modulates MYC
expression. There are also experimental links between decrease activity of the farsenoid X receptor
(FXR) and HCC [8]. FXR is a transcription factor that participates in metabolic homeostasis and
inflammation, and there is data showing decreased FXR expression in NAFLD patients. Interestingly,
liver tumors in FXR deficient mice show aberrant WNT signaling in the context of chronic liver
inflammation and fibrosis.
Autophagy has also emerged as an important cellular module in carcinogenesis. It is involved in the
elimination of damaged cellular components through lysosomal degradation and it is capable of
inducing programmed cell death. There is evidence that links global inhibition of autophagy in the
liver to steatosis, which is supported by data on impaired autophagy in experimental models of HCC.
Theoretically, restoration of autophagy could be beneficial to counteract the pro-tumorigenic effects of
NASH [9].
3. Oxidative stress: Fat accumulation in hepatocytes induces the generation of ROS that can interfere
with mitochondrial function, induce ER stress and generate genotoxins such as lipid peroxides.
Damaged DNA within hepatocytes is a potential trigger of malignant transformation and the expansion
of the progenitor cell compartment. Numerous studies implicate methionine metabolism and
s-adenosylmethionine (SAM) in HCC development [10]. MAT1A-deficient mice develop progressive
NAFLD and HCC. These mice have a marked reduction in SAM levels and increased lipid peroxides
in the serum, consistent with increased oxidative stress. Interestingly, GNMT knockout mice exhibit
high levels of hepatic SAM, and they also develop NAFLD and HCC. In this case, it seems that SAM-
induced epigenetic disarray due to aberrant DNA methylation may significantly contribute to malignant
transformation. A combination of global DNA hypomethylation in addition to generation of ROS and
nitro-active species justify these pleiotropic effects reported for hepatic SAM levels.
The International Liver Congress™ 2015 • Vienna, Austria • April 22–23, 2015 79
