MiR-139-5p is associated with poor prognosis and regulates glycolysis by repressing PKM2 in gallbladder carcinoma.

Abstract

Gallbladder carcinoma (GBC) is the most highly aggressive cancer of biliary tract, but effective therapeutics are lacking. Emerging evidence has unveiled that miR-139-5p is aberrantly downregulated in cancers, including GBC. However, the functions and mechanisms of miR-139-5p in GBC remain unclear. MiR-139-5p-overexpression was established in GBC cell lines, after which cell proliferation, migration, invasion, colony formation, and glucose metabolism were assayed in vitro. Subsequently, bioinformatics prediction and dual-luciferase reporter were performed to confirm that pyruvate kinase M2 (PKM2) was a direct target of miRNA-139-5p. Xenograft mouse models were applied to investigate the role of miR-139-5p in GBC tumourigenicity in vivo. In situ hybridization and immunohistochemical assays were performed to determine the relationships among miR-139-5p, PKM2 expression and clinical malignancies in GBC samples. We found that miR-139-5p was substantially downregulated in GBC tissues. Low expression of miR-139-5p was significantly associated with poor clinical outcomes. GBC cell proliferation, migration, and invasion could be inhibited by overexpression of miR-139-5p either in vitro or in vivo. In addition, miR-139-5p overexpression could directly inhibit PKM2 expression and lead to suppression of glucose consumption, lactate production, and cellular ATP levels. Moreover, PKM2 was frequently upregulated in GBC and correlated with poor prognosis. Mechanistically, miRNA-139-5p inhibited cell proliferation, migration, and glycolysis in GBC, at least in part, by repressing PKM2. These results demonstrated a novel role for miR-139-5p/PKM2 in GBC progression and provided potential prognostic predictors for GBC patients.