Hepatocellular carcinoma pathogenesis: from genes to environment

Farazi, Paraskevi A.; DePinho, Ronald A.

doi:10.1038/nrc1934

Cited by 1,793 publications

(1,556 citation statements)

References 162 publications

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“…Hepatitis B virus (HBV) infects approximately two billion individuals worldwide and causes an estimated 320,000 deaths annually. Approximately 30%-50% of HBV-related deaths are attributable to HCC (1). Traditionally, chemotherapy is the primary option for the treatment of unresectable solid tumors; however, these drugs are not effective in promoting tumor regression and prolonging survival in HCC (2).…”

Section: Introductionmentioning

confidence: 99%

RGD-FasL Induces Apoptosis in Hepatocellular Carcinoma

et al. 2009

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Section: Introductionmentioning

confidence: 99%

RGD-FasL Induces Apoptosis in Hepatocellular Carcinoma

et al. 2009

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“…The risk of HCC is very high among patients with advanced liver fibrosis/cirrhosis. Recent reviews summarize the importance of p53 in HCV‐induced HCC mechanisms and how HCV infection alters p53 functions by many different pathways 21, 22. Rusyn and Lemon22 claimed that the majority of publications show that HCV replication represses p53 functions.…”

Section: Discussionmentioning

confidence: 99%

Interferon‐alpha‐induced hepatitis C virus clearance restores p53 tumor suppressor more than direct‐acting antivirals

Aydın

Chatterjee

Chandra

et al. 2017

Hepatology Communications

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The mechanism why hepatitis C virus (HCV) clearance by direct‐acting antivirals (DAAs) does not eliminate the risk of hepatocellular carcinoma (HCC) among patients with advanced cirrhosis is unclear. Many viral and bacterial infections degrade p53 in favor of cell survival to adapt an endoplasmic reticulum (ER)‐stress response. In this study, we examined whether HCV clearance by interferon‐alpha or DAAs normalizes the ER stress and restores the expression of p53 tumor suppressor in cell culture. We found that HCV infection induces chronic ER stress and unfolded protein response in untransformed primary human hepatocytes. The unfolded protein response induces chaperone‐mediated autophagy (CMA) in infected primary human hepatocytes and Huh‐7.5 cells that results in degradation of p53 and induced expression of mouse double minute 2 (Mdm2). Inhibition of p53/Mdm2 interactions by small molecule (nutlin‐3) or silencing Mdm2 did not rescue the p53 degradation, indicating that HCV infection induces degradation of p53 independent of the Mdm2 pathway. Interestingly, we found that HCV infection degrades p53 in a lysosome‐dependent mechanism because lysosome‐associated membrane protein 2A silencing restored p53 degradation. Our results show that HCV clearance induced by interferon‐alpha‐based antiviral therapies normalizes the ER‐stress response and restores p53, whereas HCV clearance by DAAs does neither. We show that decreased expression of p53 in HCV‐infected cirrhotic liver is associated with expression of chaperones associated with ER stress and the CMA response. Conclusion: HCV‐induced ER stress and CMA promote p53 degradation in advanced liver cirrhosis. HCV clearance by DAAs does not restore p53, which provides a potential explanation for why a viral cure by DAAs does not eliminate the HCC risk among patients with advanced liver disease. We propose that resolving the ER‐stress response is an alternative approach to reducing HCC risk among patients with cirrhosis after viral cure. (Hepatology Communications 2017;1:256‐269)

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“…Also signaling pathways like EGFR, VEGFR, Met and intracellular mediators such as Ras and Akt/mTORC1 may play a role in HCC development and progression [104,105]. With no common mutations in coding genes that can account for all cases of HCC, it is likely that epigenetic changes are key driving mechanisms of HCC development [106].…”

Section: Genetic Epigenetic and Signaling Drivers Of Liver Cancer Amentioning

confidence: 99%

Organ-Specific Cancer Metabolism and Its Potential for Therapy

Elia

Schmieder

Christen

et al. 2015

Handbook of Experimental Pharmacology

104

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KEYWORDS:Cancer metabolism, metabolic therapy, tissue specific metabolism, genetic drivers, epigenetic drivers, microenvironment, Warburg effect, reverse Warburg effect, mixed Warburg effect, triple-negative breast cancer, estrogen receptor positive breast cancer; prostate cancer, liver cancer, gluconeogenesis, fatty acid metabolism, glucose metabolism, glutamine metabolism, serine metabolism, metabolic normalization, metabolic depletion ABSTRACTTargeting the metabolism of cancer cells has the potential to lead to major advances in tumor therapy. Numerous promising metabolic drug targets have been identified. Yet, it has emerged that there is no singular metabolism that defines the oncogenic state of the cell. Rather, the metabolism of cancer cells is a function of the requirements of a tumor. Hence, the tissue of origin, the (epi)genetic drivers, aberrant signaling, and the microenvironment all together define these metabolic requirements. In this chapter we discuss in light of (epi)genetic, signaling, and environmental factors the diversity in cancer metabolism based on triple-negative and estrogen receptor positive breast cancer, early and late stage prostate cancer, and liver cancer. These types of cancer all display distinct and partially opposing metabolic behaviors (e.g. Warburg versus reverse Warburg metabolism). Yet, for each of the cancers their distinct metabolism supports the oncogenic phenotype. Finally, we will assess the therapeutic potential of metabolism based on the concepts of metabolic normalization and metabolic depletion.

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Hepatocellular carcinoma pathogenesis: from genes to environment

Cited by 1,793 publications

References 162 publications

RGD-FasL Induces Apoptosis in Hepatocellular Carcinoma

RGD-FasL Induces Apoptosis in Hepatocellular Carcinoma

Interferon‐alpha‐induced hepatitis C virus clearance restores p53 tumor suppressor more than direct‐acting antivirals

Organ-Specific Cancer Metabolism and Its Potential for Therapy

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