Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, CH-1211 Geneva, Switzerland.
Service of Clinical Pathology, Institute of Pathology, Lausanne University Hospital, University of Lausanne, CH-1011 Lausanne, Switzerland.
Cells. 2022 Sep 14;11(18):2860. doi: 10.3390/cells11182860.
MiR-22 is mostly considered as a hepatic tumor-suppressor microRNA based on in vitro analyses. Yet, whether miR-22 exerts a tumor-suppressive function in the liver has not been investigated in vivo. Herein, in silico analyses of miR-22 expression were performed in hepatocellular carcinomas from human patient cohorts and different mouse models. Diethylnitrosamine-induced hepatocellular carcinomas were then investigated in lean and diet-induced obese miR-22-deficient mice. The proteome of liver tissues from miR-22-deficient mice prior to hepatocellular carcinoma development was further analyzed to uncover miR-22 regulated factors that impact hepatocarcinogenesis with miR-22 deficiency. MiR-22 downregulation was consistently observed in hepatocellular carcinomas from all human cohorts and mouse models investigated. The time of appearance of the first tumors was decreased and the number of tumoral foci induced by diethylnitrosamine was significantly increased by miR-22-deficiency in vivo, two features which were further drastically exacerbated with diet-induced obesity. At the molecular level, we provide evidence that the loss of miR-22 significantly affects the energetic metabolism and mitochondrial functions of hepatocytes, and the expression of tumor-promoting factors such as thrombospondin-1. Our study demonstrates that miR-22 acts as a hepatic tumor suppressor in vivo by restraining pro-carcinogenic metabolic deregulations through pleiotropic mechanisms and the overexpression of relevant oncogenes.
miR-22 主要被认为是一种具有抑瘤作用的肝肿瘤 microRNA，这是基于体外分析得出的结论。然而，miR-22 是否在体内发挥肝肿瘤抑制作用尚未进行研究。在此，通过对来自人类患者队列和不同小鼠模型的肝细胞癌的 miR-22 表达进行计算机分析。然后在 lean 和 diet-induced obese 两种 miR-22 缺陷型小鼠中研究二乙基亚硝胺诱导的肝细胞癌。进一步分析 miR-22 缺陷型小鼠在发生肝细胞癌之前的肝脏组织蛋白质组，以揭示 miR-22 调控的影响 miR-22 缺陷型肝细胞癌发生的因子。miR-22 的下调在所有研究的人类队列和小鼠模型的肝细胞癌中均一致观察到。miR-22 缺陷型小鼠的体内研究表明，miR-22 缺陷型小鼠中首次出现肿瘤的时间提前，且二乙基亚硝胺诱导的肿瘤灶数量明显增加，而饮食诱导肥胖进一步显著加剧了这两个特征。在分子水平上，我们提供的证据表明，miR-22 的缺失显著影响了肝细胞的能量代谢和线粒体功能，以及促肿瘤因子如血小板反应蛋白-1 的表达。我们的研究表明，miR-22 通过多种机制和相关癌基因的过表达来抑制致癌代谢失调，从而在体内发挥肝肿瘤抑制作用。
