miR-27a is a master regulator of metabolic reprogramming and chemoresistance in colorectal cancer

• Published in: British journal of cancer Vol. 122; no. 9; pp. 1354 - 1366
• Main Authors: Barisciano, Giovannina, Colangelo, Tommaso, Rosato, Valeria, Muccillo, Livio, Taddei, Maria Letizia, Ippolito, Luigi, Chiarugi, Paola, Galgani, Mario, Bruzzaniti, Sara, Matarese, Giuseppe, Fassan, Matteo, Agostini, Marco, Bergamo, Francesca, Pucciarelli, Salvatore, Carbone, Annalucia, Mazzoccoli, Gianluigi, Colantuoni, Vittorio, Bianchi, Fabrizio, Sabatino, Lina
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2020; Nature Publishing Group
• Subjects: 631/337/384/331; 631/67/2327; Adult; Aged; Aged, 80 and over; Biomedical and Life Sciences; Biomedicine; Cancer; Cancer Research; Cell proliferation; Cell Proliferation - drug effects; Cell survival; Cellular Reprogramming - drug effects; Cellular Reprogramming - genetics; Chemoresistance; Chemotherapy; Cisplatin - pharmacology; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; Colorectal Neoplasms - radiotherapy; Drug Resistance; Drug Resistance, Neoplasm - drug effects; Epidemiology; Female; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Glycolysis; HCT116 Cells; Humans; Male; Metabolism; MicroRNAs - genetics; Middle Aged; miRNA; Mitochondria; Molecular Medicine; Oncology; Oxidative phosphorylation; Phosphorylation; Protein Kinases - genetics; Signal transduction; Signal Transduction - drug effects; TOR protein; TOR Serine-Threonine Kinases - genetics; Tumors
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/s41416-020-0773-2

Background Metabolic reprogramming towards aerobic glycolysis in cancer supports unrestricted cell proliferation, survival and chemoresistance. The molecular bases of these processes are still undefined. Recent reports suggest crucial roles for microRNAs. Here, we provide new evidence of the implication of miR-27a in modulating colorectal cancer (CRC) metabolism and chemoresistance. Methods A survey of miR-27a expression profile in TCGA-COAD dataset revealed that miR-27a-overexpressing CRCs are enriched in gene signatures of mitochondrial dysfunction, deregulated oxidative phosphorylation, mTOR activation and reduced chemosensitivity. The same pathways were analysed in cell lines in which we modified miR-27a levels. The response to chemotherapy was investigated in an independent cohort and cell lines. Results miR-27a upregulation in vitro associated with impaired oxidative phosphorylation, overall mitochondrial activities and slight influence on glycolysis. miR-27a hampered AMPK, enhanced mTOR signalling and acted in concert with oncogenes and tumour cell metabolic regulators to force an aerobic glycolytic metabolism supporting biomass production, unrestricted growth and chemoresistance. This latter association was confirmed in our cohort of patients and cell lines. Conclusions We disclose an unprecedented role for miR-27a as a master regulator of cancer metabolism reprogramming that impinges on CRC response to chemotherapy, underscoring its theragnostic properties.