Over-expression of the miR-483-3p overcomes the miR-145/TP53 pro-apoptotic loop in hepatocellular carcinoma

Lupini, L. et al. (2016) Over-expression of the miR-483-3p overcomes the miR-145/TP53 pro-apoptotic loop in hepatocellular carcinoma. Oncotarget, 7(21), pp. 31361-31371. (doi: 10.18632/oncotarget.8913) (PMID:27120784) (PMCID:PMC5058762)

187975.pdf - Published Version
Available under License Creative Commons Attribution.



The miR-145-5p, which induces TP53-dependent apoptosis, is down-regulated in several tumors, including hepatocellular carcinomas (HCCs), but some HCCs show physiological expression of this miR. Here we demonstrate that in HCC cells carrying wild-type TP53 the steady activation of the miR-145 signaling selects clones resistant to apoptosis via up-regulation of the oncogenic miR-483-3p. Expression of the miR-145-5p and of the miR-483-3p correlated negatively in non-neoplastic liver (n=41; ρ=-0.342, P=0.028), but positively in HCCs (n=21; ρ=0.791, P<0.0001), which we hypothesized to be due to impaired glucose metabolism in HCCs versus normal liver. In fact, when liver cancer cells were grown in low glucose, miR-145-5p lowered miR-483-3p expression, allowing apoptosis, whereas when cells were grown in high glucose the levels of miR-483-3p increased, reducing the apoptotic rate. This indicates that depending on glucose availability the miR-145-5p has double effects on the miR-483-3p, either inhibitory or stimulatory. Moreover, resistance to apoptosis in clones overexpressing both miR-145-5p and miR-483-3p was abrogated by silencing the miR-483-3p. Our data highlight a novel mechanism of resistance to apoptosis in liver cancer cells harbouring wild type TP53 and suggest a potential role of miR-145-5p and miR-483-3p as druggable targets in a subset of HCCs.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Braconi, Dr Chiara
Authors: Lupini, L., Pepe, F., Ferracin, M., Braconi, C., Callegari, E., Pagotto, S., Spizzo, R., Zagatti, B., Lanuti, P., Fornari, F., Ghasemi, R., Mariani-Costantini, R., Bolondi, L., Gramantieri, L., Calin, G. A., Sabbioni, S., Visone, R., Veronese, A., and Negrini, M.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Oncotarget
Publisher:Impact Journals
ISSN (Online):1949-2553
Published Online:22 April 2016
Copyright Holders:Copyright © 2016 The Authors
First Published:First published in Oncotarget 7(21): 31361-31371
Publisher Policy:Reproduced under a Creative Commons License

University Staff: Request a correction | Enlighten Editors: Update this record