Mir-21 Suppression Promotes Mouse Hepatocarcinogenesis

Simple Summary: Hepatocellular carcinoma (HCC) is a frequent cancer of the liver with limited therapeutic options. MicroRNAs are a class of small molecules regulating a wide range of cellular processes that are important for cancer development. Among these microRNAs, miR-21 is strongly upregulated in almost all human cancers including HCC, and is considered as a strong driver of cancer development, suggesting that its pharmacological inhibition might represent a potential therapy. In this study, we show that deletion of miR-21 in genetically engineered mice promotes instead the development of HCC in several mouse models of this liver cancer. We further show that the lack of miR-21 is associated with increases in the expression of oncogenes such as Cdc25a, subtle deregulations of the MAPK, HiPPO, and STAT3 signaling pathways, as well as alterations of the inflammatory/immune anti-tumoral responses in the liver, which overtime contribute to enhanced tumorigenesis and progression toward malignancy. These results call for cautiousness when considering miR-21 inhibition for therapeutic purposes in HCC. The microRNA 21 (miR-21) is upregulated in almost all known human cancers and is considered a highly potent oncogene and potential therapeutic target for cancer treatment. In the liver, miR-21 was reported to promote hepatic steatosis and inflammation, but whether miR-21 also drives hepatocarcinogenesis remains poorly investigated in vivo. Here we show using both carcinogen (Diethylnitrosamine, DEN) or genetically (PTEN deficiency)-induced mouse models of hepatocellular carcinoma (HCC), total or hepatocyte-specific genetic deletion of this microRNA fosters HCC development-contrasting the expected oncogenic role of miR-21. Gene and protein expression analyses of mouse liver tissues further indicate that total or hepatocyte-specific miR-21 deficiency is associated with an increased expression of oncogenes such as Cdc25a, subtle deregulations of the MAPK, HiPPO, and STAT3 signaling pathways, as well as alterations of the inflammatory/immune anti-tumoral responses in the liver. Together, our data show that miR-21 deficiency promotes a pro-tumoral microenvironment, which over time fosters HCC development via pleiotropic and complex mechanisms. These results question the current dogma of miR-21 being a potent oncomiR in the liver and call for cautiousness when considering miR-21 inhibition for therapeutic purposes in HCC.