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Research Paper|Volume 13, Issue 10|pp 14433—14455

Chronic alcohol exposure promotes HCC stemness and metastasis through β-catenin/miR-22-3p/TET2 axis

Danlei Chen1,2, Yan Yan1, Xinyi Wang1,3, Suzhi Li1, Yan Liu1, Dandan Yu1, Yongjing He1, Ruiqing Deng1, Yakun Liu1, Mei Xu4, Jia Luo5, Hongjun Gao1,3, Siying Wang1
  • 1School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, Anhui, China
  • 2The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, Anhui, China
  • 3Department of Pulmonary Oncology, The Fifth Medical Center of Chinese PLA General Hospital, Fengtai, Beijing 100071, China
  • 4Department of Pharmacology and Nutritional Sciences, University of Kentucky, College of Medicine, Lexington, KY 40536, USA
  • 5Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
Received: September 18, 2020Accepted: March 13, 2021Published: May 21, 2021
https://doi.org/10.18632/aging.203059

Copyright: © 2021 Chen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Hepatocellular Carcinoma (HCC) patients usually have a high rate of relapse and metastasis. Alcohol, a risk factor for HCC, promotes the aggressiveness of HCC. However, the basic mechanism is still unclear. We used HCC cells and an orthotopic liver tumor model of HCC-LM3 cells for BALB/C nude mice to study the mechanism of alcohol-induced HCC progression. We showed that chronic alcohol exposure promoted HCC cells metastasis and pulmonary nodules formation. First, we identified miR-22-3p as an oncogene in HCC, which promoted HCC cells stemness, tumor growth, and metastasis. Further, we found that miR-22-3p directly targeted TET2 in HCC. TET2, a dioxygenase involved in cytosine demethylation, has pleiotropic roles in hematopoietic stem cells self-renewal. In clinic HCC specimen, TET2 expression was not only decreased by alcohol consumption, but also inversely correlated with miR-22-3p levels. Then, we demonstrated that TET2 depletion promoted HCC cells stemness, tumor growth and metastasis. Furthermore, we identified that β-catenin was an upstream activator of miR-22-3p. In conclusion, this study suggests that chronic alcohol exposure promotes HCC progression and β-catenin/miR-22-3p/TET2 regulatory axis plays an important role in alcohol-promoted HCC malignancy.