Mir-21 Suppression Promotes Mouse Hepatocarcinogenesis

• Published in: Cancers Vol. 13; no. 19; p. 4983
• Main Authors: Correia de Sousa, Marta, Calo, Nicolas, Sobolewski, Cyril, Gjorgjieva, Monika, Clément, Sophie, Maeder, Christine, Dolicka, Dobrochna, Fournier, Margot, Vinet, Laurent, Montet, Xavier, Dufour, Jean-François, Humar, Bostjan, Negro, Francesco, Sempoux, Christine, Foti, Michelangelo
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 04.10.2021; MDPI
• Subjects: Animal models; Animals; Cancer therapies; Carcinogens; Cloning; Diethylnitrosamine; DNA methylation; Fatty liver; fibrosis; Gene expression; Genetic engineering; HCC; Hepatocellular carcinoma; Histology; Inflammation; Investigations; Liver cancer; Liver diseases; Malignancy; MAP kinase; Microenvironments; microRNA 21; MicroRNAs; miRNA; Mutation; oncogenes; PTEN protein; Signal transduction; Software; Stat3 protein; Steatosis; Therapeutic applications; tumor suppressors; Tumorigenesis; Tumors; United States > US; inflammation; PTEN; microRNA 21; oncogenes; tumor suppressors; HCC; immune cells; fibrosis
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers13194983

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 , 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.