Regulation of autophagy and its impact in the development and progression of hepatocellular cancer.

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The aim was to clarify the relationship between apoptosis and autophagy in the pathogenesis of non-alcoholic steatohepatitis, and also in the treatment of hepatocellular carcinoma (HCC). Excess free fatty acids suppressed autophagic flux in hepatocytes and induced apoptosis by increasing endoplasmic reticulum stress. Hepatocyte-specific Mcl-1 knockout mice revealed that chronically increased hepatocyte apoptosis leads to liver fibrosis and cancer, suggesting that, in the pathogenesis of steatohepatitis, continuous hepatocyte apoptosis induced by autophagy impairment contributes to hepatic fibrogenesis and carcinogenesis. Finally, sorafenib, a multikinase inhibitor for the treatment of HCC, enhanced autophagic activity, which then inhibited apoptosis in hepatoma cells. In conclusion, autophagy may be a double-edged sword in the liver cancer development and progression; the promotion promotes the survival of the cancer cells while the restraint promotes the outbreak of cancer.