Abstract
The liver acts as a hub for metabolic reactions to keep a homeostatic balance during development and growth. The process of liver cancer development, although poorly understood, is related to different etiologic factors like toxins, alcohol, or viral infection. At the molecular level, liver cancer is characterized by a disruption of cell cycle regulation through many molecular mechanisms. In this review, we focus on the mechanisms underlying the lack of regulation of the cell cycle during liver cancer, focusing mainly on hepatocellular carcinoma (HCC). We also provide a brief summary of novel therapies connected to cell cycle regulation.
Highlights
Technology and Research), 61 Biopolis Drive, Proteos#3-09, Singapore 138673, Singapore; National University of Singapore (NUS), Department of Biochemistry, Singapore 117597, Singapore
But can repress p21 expression via decreases of Sp1 activity [203,204]. These results reveal that p21 acts as a brake of the cell cycle and its down regulation is required for hepatocarcinogenesis induced by hepatitis viruses, mitogens (JNK, MAPK, ...) [205] or toxic metabolites accumulation induced by tyrosinemia type 1 [206,207]
Skp2 is targeted for degradation by the APC/C complex, itself regulated by Emi1, which is frequently overexpressed in hepatocellular carcinoma (HCC) like Skp2. p27 is down regulated in HCC, its overexpression is a result of phosphorylation on T157 by Akt/PKB, leading to export of p27 to the cytoplasm where it is sequestered by Cdk4/cyclin D complexes
Summary
The liver is located at a strategic position in the human body and regulates metabolic homeostasis by producing energy and molecules used by other cells in nearby or very distant tissues. Primary liver cancers display an important epidemiologic trend where the prevalence is related to different risks and etiologic factors in different geographic regions of the world [10]. Many studies suggested that the risk factors related to liver cancer are alcohol abuse, smoking, exposure to aflatoxins, sex, ethnicity, as well as infection by hepatitis B (HBV) and C viruses (HCV) [11,12,13]. Whereas heavy alcohol intake is the main cause of cirrhosis, long-term exposure to aflatoxins and HBV and/or HCV infection increase the frequency of liver cancer development and HCC [14,15,16,17]. With the goal to give insight into potent cell cycle based therapies against HCC, we will dissect cell cycle regulation and its particularities observed in the normal and pathologic liver
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