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

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 signali...

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Autores principales: Lupini, Laura, Pepe, Felice, Ferracin, Manuela, Braconi, Chiara, Callegari, Elisa, Pagotto, Sara, Spizzo, Riccardo, Zagatti, Barbara, Lanuti, Paola, Fornari, Francesca, Ghasemi, Reza, Mariani-Costantini, Renato, Bolondi, Luigi, Gramantieri, Laura, Calin, George A., Sabbioni, Silvia, Visone, Rosa, Veronese, Angelo, Negrini, Massimo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5058762/
https://www.ncbi.nlm.nih.gov/pubmed/27120784
http://dx.doi.org/10.18632/oncotarget.8913
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author Lupini, Laura
Pepe, Felice
Ferracin, Manuela
Braconi, Chiara
Callegari, Elisa
Pagotto, Sara
Spizzo, Riccardo
Zagatti, Barbara
Lanuti, Paola
Fornari, Francesca
Ghasemi, Reza
Mariani-Costantini, Renato
Bolondi, Luigi
Gramantieri, Laura
Calin, George A.
Sabbioni, Silvia
Visone, Rosa
Veronese, Angelo
Negrini, Massimo
author_facet Lupini, Laura
Pepe, Felice
Ferracin, Manuela
Braconi, Chiara
Callegari, Elisa
Pagotto, Sara
Spizzo, Riccardo
Zagatti, Barbara
Lanuti, Paola
Fornari, Francesca
Ghasemi, Reza
Mariani-Costantini, Renato
Bolondi, Luigi
Gramantieri, Laura
Calin, George A.
Sabbioni, Silvia
Visone, Rosa
Veronese, Angelo
Negrini, Massimo
author_sort Lupini, Laura
collection PubMed
description 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.
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spelling pubmed-50587622016-10-15 Over-expression of the miR-483-3p overcomes the miR-145/TP53 pro-apoptotic loop in hepatocellular carcinoma Lupini, Laura Pepe, Felice Ferracin, Manuela Braconi, Chiara Callegari, Elisa Pagotto, Sara Spizzo, Riccardo Zagatti, Barbara Lanuti, Paola Fornari, Francesca Ghasemi, Reza Mariani-Costantini, Renato Bolondi, Luigi Gramantieri, Laura Calin, George A. Sabbioni, Silvia Visone, Rosa Veronese, Angelo Negrini, Massimo Oncotarget Research Paper 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. Impact Journals LLC 2016-04-22 /pmc/articles/PMC5058762/ /pubmed/27120784 http://dx.doi.org/10.18632/oncotarget.8913 Text en Copyright: © 2016 Lupini et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Lupini, Laura
Pepe, Felice
Ferracin, Manuela
Braconi, Chiara
Callegari, Elisa
Pagotto, Sara
Spizzo, Riccardo
Zagatti, Barbara
Lanuti, Paola
Fornari, Francesca
Ghasemi, Reza
Mariani-Costantini, Renato
Bolondi, Luigi
Gramantieri, Laura
Calin, George A.
Sabbioni, Silvia
Visone, Rosa
Veronese, Angelo
Negrini, Massimo
Over-expression of the miR-483-3p overcomes the miR-145/TP53 pro-apoptotic loop in hepatocellular carcinoma
title Over-expression of the miR-483-3p overcomes the miR-145/TP53 pro-apoptotic loop in hepatocellular carcinoma
title_full Over-expression of the miR-483-3p overcomes the miR-145/TP53 pro-apoptotic loop in hepatocellular carcinoma
title_fullStr Over-expression of the miR-483-3p overcomes the miR-145/TP53 pro-apoptotic loop in hepatocellular carcinoma
title_full_unstemmed Over-expression of the miR-483-3p overcomes the miR-145/TP53 pro-apoptotic loop in hepatocellular carcinoma
title_short Over-expression of the miR-483-3p overcomes the miR-145/TP53 pro-apoptotic loop in hepatocellular carcinoma
title_sort over-expression of the mir-483-3p overcomes the mir-145/tp53 pro-apoptotic loop in hepatocellular carcinoma
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5058762/
https://www.ncbi.nlm.nih.gov/pubmed/27120784
http://dx.doi.org/10.18632/oncotarget.8913
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