Journal of Cellular and Molecular Medicine
Alcohol is a risk factor for hepatocellular carcinoma (HCC). However, the molecular mechanism by which chronic alcohol consumption contributes to HCC is not well understood. The purpose of the study was to demonstrate the effects of chronic ethanol exposure on the damage of human normal hepatocytes. Our data showed that chronic exposure of hepatocytes with ethanol induced changes similar to transformed hepatocytes that is, exhibited colonies and anchorage-independent growth. These damaged hepatocytes contained high levels of reactive oxygen species (ROS) and showed induction of the SATB2 gene. Furthermore, damaged hepatocytes gained the phenotypes of CSCs which expressed stem cell markers (CD133, CD44, CD90, EpCAM, AFP and LGR5), and pluripotency maintaining factors (Sox-2, POU5F1/Oct4 and KLF-4). Ethanol exposure also induced Nanog, a pluripotency maintaining transcription factor that functions in concert with Oct4 and SOX-2. Furthermore, ethanol induced expression of EMT-related transcription factors (Snail, Slug and Zeb1), N-Cadherin, and inhibited E-cadherin expression in damaged hepatocytes. Ethanol enhanced recruitment of SATB2 to promoters of Bcl-2, Nanog, c-Myc, Klf4 and Oct4. Ethanol also induced activation of the Wnt/TCF-LEF1 pathway and its targets (Bcl-2, Cyclin D1, AXIN2 and Myc). Finally, ethanol induced hepatocellular steatosis, SREBP1 transcription, and modulated the expression of SREBP1c, ACAC, ACLY, FASN, IL-1β, IL-6, TNF-α, GPC3, FLNB and p53. These data suggest that chronic alcohol consumption may contribute towards the development of HCC by damaging normal hepatocytes with the generation of inflammatory environment, induction of SATB2, stem cell-like characteristics, and cellular steatosis.
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Yu, Wei; Ma, Yiming; Shrivastava, Sushant K.; Srivastava, Rakesh K.; and Shankar, Sharmila, "Chronic Alcohol Exposure Induces Hepatocyte Damage By Inducing Oxidative Stress, Satb2 And Stem Cell-like Characteristics, And Activating Lipogenesis" (2022). School of Medicine Faculty Publications. 1099.