4.6 Article

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

Journal

AGING-US
Volume 13, Issue 10, Pages 14433-14455

Publisher

IMPACT JOURNALS LLC

Keywords

HCC; metastasis; stemness; alcohol

Funding

  1. Project of the National Natural Sciences Foundation of China [81272258, 81572749]
  2. China Scholarship Council

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This study found that chronic alcohol exposure promotes the progression of hepatocellular carcinoma (HCC), with miR-22-3p and TET2 playing important roles in this process, affecting the stemness, tumor growth, and metastasis of HCC cells.β-catenin was identified as an upstream activator of miR-22-3p, indicating the involvement of the beta-catenin/miR-22-3p/TET2 regulatory axis in alcohol-induced HCC malignancy.
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 beta-catenin was an upstream activator of miR-22-3p. In conclusion, this study suggests that chronic alcohol exposure promotes HCC progression and beta-catenin/miR-22-3p/TET2 regulatory axis plays an important role in alcohol-promoted HCC malignancy.

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