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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...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2016
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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. |
format | Online Article Text |
id | pubmed-5058762 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
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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