MiR‐139‐5p is associated with poor prognosis and regulates glycolysis by repressing PKM 2 in gallbladder carcinoma

Abstract Objectives 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. Materials and methods 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 ( PKM 2) was a direct target of mi RNA ‐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, PKM 2 expression and clinical malignancies in GBC samples. Results 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 PKM 2 expression and lead to suppression of glucose consumption, lactate production, and cellular ATP levels. Moreover, PKM 2 was frequently upregulated in GBC and correlated with poor prognosis. Mechanistically, mi RNA ‐139‐5p inhibited cell proliferation, migration, and glycolysis in GBC , at least in part, by repressing PKM 2. Conclusions These results demonstrated a novel role for miR‐139‐5p/ PKM 2 in GBC progression and provided potential prognostic predictors for GBC patients.