School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, Anhui, China.
The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, Anhui, China.
Aging (Albany NY). 2021 May 21;13(10):14433-14455. doi: 10.18632/aging.203059.
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 -catenin was an upstream activator of miR-22-3p. In conclusion, this study suggests that chronic alcohol exposure promotes HCC progression and -catenin/miR-22-3p/TET2 regulatory axis plays an important role in alcohol-promoted HCC malignancy.
肝细胞癌 (HCC) 患者通常具有较高的复发和转移率。酒精是 HCC 的一个风险因素，它促进了 HCC 的侵袭性。然而，其基本机制仍不清楚。我们使用 HCC 细胞和 HCC-LM3 细胞的原位肝肿瘤模型，研究了酒精诱导 HCC 进展的机制。我们发现慢性酒精暴露促进 HCC 细胞转移和肺结节形成。首先，我们鉴定出 miR-22-3p 是 HCC 的致癌基因，它促进 HCC 细胞的干性、肿瘤生长和转移。进一步，我们发现 miR-22-3p 直接靶向 HCC 中的 TET2。TET2 是一种参与胞嘧啶去甲基化的双加氧酶，在造血干细胞自我更新中具有多种作用。在临床 HCC 标本中，TET2 的表达不仅被酒精消耗所抑制，而且与 miR-22-3p 的水平呈负相关。然后，我们证明 TET2 的缺失促进了 HCC 细胞的干性、肿瘤生长和转移。此外，我们确定 β-连环蛋白是 miR-22-3p 的上游激活物。总之，这项研究表明，慢性酒精暴露促进 HCC 的进展，并且 β-连环蛋白/miR-22-3p/TET2 调节轴在酒精促进的 HCC 恶性转化中发挥重要作用。
