Roles of p53 in extrinsic factor-induced liver carcinogenesis

Abstract

How to cite this article: Link T, Iwakuma T. Roles of p53 in extrinsic factor-induced liver carcinogenesis. Hepatoma Res 2017;3:95-104.Liver cancer remains one of the most common human cancers with a high mortality rate. Therapies for hepatocellular carcinoma (HCC) remain ineffective, due to the heterogeneity of HCC with regard to both the etiology and mutation spectrum, as well as its chemotherapy resistant nature; thus surgical resection and liver transplantation remain the gold standard of patient care. The most common etiologies of HCC are extrinsic factors. Humans have multiple defense mechanisms against extrinsic factor-induced carcinogenesis, of which tumor suppressors play crucial roles in preventing normal cells from becoming cancerous. The tumor suppressor p53 is one of the most frequently mutated genes in liver cancer. p53 regulates expression of genes involved in cell cycle progression, cell death, and cellular metabolism to avert tumor development due to carcinogens. This review article mainly summarizes extrinsic factors that induce liver cancer and potentially have etiological association with p53, including aflatoxin B1, vinyl chloride, non-alcoholic fatty liver disease, iron overload, and infection of hepatitis viruses. ReviewThis is an open access article distributed under the terms of the Creative Commons AttributionNonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms. Dr. Iwakuma's primary research focuses on the field of cancer research, specifically on cancer progression and metastasis in bone and soft tissue sarcoma, head and neck squamous cell carcinoma, and liver cancer. Over 50% of human cancer has mutations in the tumor suppressor p53 which regulates cell cycle progression, cell death, senescence, chromosome integrity, DNA repair, and metastasis. Therefore, understanding of the pathway involved in the regulation of p53 is essential for discovering novel cancer therapies. With special focus on the tumor suppressor p53 pathway, Dr. Iwakuma dissects the mechanism of cancer progression using genetically engineered mice, as well as tumor transplantation models, and applies disease models to translational research, to ultimately cure cancer.

Tumor suppressor ZHX2 inhibits NAFLD–HCC progression via blocking LPL-mediated lipid uptake

“…Accumulating evidence demonstrated that tumor suppressor genes (TSGs) closely regulate cell proliferation and differentiation, as well as lipid metabolisms and NAFLD. TP53, a TSG and one of the most frequently mutated genes in HCC, inhibits the expression of cellular metabolism-regulating genes to prevent tumor development [6]. Liver-specific deficiency of PTEN, another well-known TSG, promotes hepatic expression of adipocyte-specific genes and lipogenesis and beta-oxidation-related genes [7], leading to steatohepatitis and HCC [8].…”

Analysis of TP53 gene mutations demonstrates that aflatoxin is a risk factor for hepatocellular carcinoma in Guatemala

“…Non-alcoholic steatohepatitis (NASH), involving mechanisms such as upregulation of TP53 activity with increased mRNA levels of the p21 and p66ShC proteins, which are associated with fibrosis severity (33). The current study also identified somatic mutations in other known HCC driver genes, including beta-catenin (CTNNB1),, ARID1A, ARID2, AXIN1, among others.…”

“…(31,32) Etiological factors, in addition to AFB 1 ,such as HBV, HCV and alcohol have been implicated in generating TP53 mutations in HCC. (31,33) Inactivation of p53 by core proteins produced by HBV (e.g.…”

“…NS3 and NS5A) may lead to the development and progression of HCCs. (33). Furthermore, in animal studies, p53 has been implicated in the progression of steatosis to associations between some known risk factors and mutational patterns.…”

Screening of Natural Stilbene Oligomers from Vitis vinifera for Anticancer Activity on Human Hepatocellular Carcinoma Cells

“…There is currently no effective treatment for HCC due to the high heterogeneity of the cancer. Thus, extrinsic factors and different mutations contribute to the induction of liver cancer [3,4]. Among the genetic factors, mutations in the p53 tumor suppressor gene (TP53) are frequent, especially in HCC from populations exposed to environmental carcinogens, such as dietary aflatoxin B1 [5].…”