Abstract 3810: MicroRNA-483-5p inhibits cell steatosis and fibrosis by targeting PPARa, TIMP2 and HCC cell proliferation by modulating notch signaling

Abstract

MicroRNAs (miRNAs) are small non-coding RNA molecules that bind with 3’ untranslated regions (UTRs) of genes and regulate expression. Downregulation of miR-483-5p (miR-483), is associated with the progression of hepatocellular carcinoma (HCC). However, the molecular and mechanistic role of miR-483 in nonalcoholic fatty liver disease (NAFLD), alcoholic fatty liver diseases (AFLD), and HCC remain elusive. In the current study, we investigated the biological significance of miR-483-5p in NAFLD, AFLD, and HCC in vitro and in vivo. Our data show that the expression of miR-483 was downregulated in tumor samples from HCC patients. Overexpression of miR-483 in HCC cells dysregulated Notch signaling, inhibited cell proliferation/migration, induced apoptosis, and increased sensitivity towards sorafenib/regorafenib; anti-HCC drugs. Interestingly, miR-483 overexpression downregulated cell steatosis and fibrogenic signaling in HCC cells. Mechanistically, miR-483 targets peroxisome proliferator-activated receptor α (PPARα) and tissue inhibitor of metalloproteinases 2 (TIMP2) gene expression by binding to 3’-UTR and suppress cell steatosis and fibrosis. Down-regulation of miR-483 was observed in mice fed with a high-fat diet (HFD) or alcohol which lead to increased hepatic steatosis/fibrosis. Our data suggest that miR-483 inhibits cell steatosis and fibrogenic signaling, and functions as a tumor suppressor in HCC. Therefore, miR-483 may be used as a novel therapeutic target for NAFLD/AFLD/HCC management in patients with fatty live diseases/HCC. Citation Format: Suryakant Niture, Sashi Gadi, Qi Qi, Maxwell Gyamfi, Leslimar Rios-Colon, Rency Varghese, Habtom Ressom, Deepak Kumar. MicroRNA-483-5p inhibits cell steatosis and fibrosis by targeting PPARa, TIMP2 and HCC cell proliferation by modulating notch signaling. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3810.