Correia de Sousa, MartaMartaCorreia de SousaCalo, NicolasNicolasCaloSobolewski, CyrilCyrilSobolewskiGjorgjieva, MonikaMonikaGjorgjievaClément, SophieSophieClémentMaeder, ChristineChristineMaederDolicka, DobrochnaDobrochnaDolickaFournier, MargotMargotFournierVinet, LaurentLaurentVinetMontet, XavierXavierMontetDufour, Jean-FrançoisJean-FrançoisDufourHumar, BostjanBostjanHumarNegro, FrancescoFrancescoNegroSempoux, ChristineChristineSempouxFoti, MichelangeloMichelangeloFoti2024-10-052024-10-052021-10-04https://boris-portal.unibe.ch/handle/20.500.12422/53744The 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.enHCC PTEN fibrosis immune cells inflammation microRNA 21 oncogenes tumor suppressors600 - Technology::610 - Medicine & healtharticle10.48350/1601823463846710.3390/cancers13194983