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miR-125b Upregulates miR-34a and Sequentially Activates Stress Adaption and Cell Death Mechanisms in Multiple Myeloma
miR-125b, ubiquitously expressed and frequently dysregulated in several tumors, has gained special interest in the field of cancer research, displaying either oncogenic or oncosuppressor potential based on tumor type. We have previously demonstrated its tumor-suppressive role in multiple myeloma (MM...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society of Gene & Cell Therapy
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6479071/ https://www.ncbi.nlm.nih.gov/pubmed/31009917 http://dx.doi.org/10.1016/j.omtn.2019.02.023 |
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author | Misso, Gabriella Zarone, Mayra Rachele Lombardi, Angela Grimaldi, Anna Cossu, Alessia Maria Ferri, Carmela Russo, Margherita Vuoso, Daniela Cristina Luce, Amalia Kawasaki, Hiromichi Di Martino, Maria Teresa Virgilio, Antonella Festa, Agostino Galeone, Aldo De Rosa, Giuseppe Irace, Carlo Donadelli, Massimo Necas, Alois Amler, Evzen Tagliaferri, Pierosandro Tassone, Pierfrancesco Caraglia, Michele |
author_facet | Misso, Gabriella Zarone, Mayra Rachele Lombardi, Angela Grimaldi, Anna Cossu, Alessia Maria Ferri, Carmela Russo, Margherita Vuoso, Daniela Cristina Luce, Amalia Kawasaki, Hiromichi Di Martino, Maria Teresa Virgilio, Antonella Festa, Agostino Galeone, Aldo De Rosa, Giuseppe Irace, Carlo Donadelli, Massimo Necas, Alois Amler, Evzen Tagliaferri, Pierosandro Tassone, Pierfrancesco Caraglia, Michele |
author_sort | Misso, Gabriella |
collection | PubMed |
description | miR-125b, ubiquitously expressed and frequently dysregulated in several tumors, has gained special interest in the field of cancer research, displaying either oncogenic or oncosuppressor potential based on tumor type. We have previously demonstrated its tumor-suppressive role in multiple myeloma (MM), but the analysis of molecular mechanisms needs additional investigation. The purpose of this study was to explore the effects of miR-125b and its chemically modified analogs in modulating cell viability and cancer-associated molecular pathways, also focusing on the functional aspects of stress adaptation (autophagy and senescence), as well as programmed cell death (apoptosis). Based on the well-known low microRNA (miRNA) stability in therapeutic application, we designed chemically modified miR-125b mimics, laying the bases for their subsequent investigation in in vivo models. Our study clearly confirmed an oncosuppressive function depending on the repression of multiple targets, and it allowed the identification, for the first time, of miR-125b-dependent miR-34a stimulation as a possible consequence of the inhibitory role on the interleukin-6 receptor (IL-6R)/signal transducer and activator of transcription 3 (STAT3)/miR-34a feedback loop. Moreover, we identified a pattern of miR-125b-co-regulated miRNAs, shedding light on possible new players of anti-MM activity. Finally, functional studies also revealed a sequential activation of senescence, autophagy, and apoptosis, thus indicating, for the first two processes, an early cytoprotective and inhibitory role from apoptosis activation. |
format | Online Article Text |
id | pubmed-6479071 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | American Society of Gene & Cell Therapy |
record_format | MEDLINE/PubMed |
spelling | pubmed-64790712019-05-01 miR-125b Upregulates miR-34a and Sequentially Activates Stress Adaption and Cell Death Mechanisms in Multiple Myeloma Misso, Gabriella Zarone, Mayra Rachele Lombardi, Angela Grimaldi, Anna Cossu, Alessia Maria Ferri, Carmela Russo, Margherita Vuoso, Daniela Cristina Luce, Amalia Kawasaki, Hiromichi Di Martino, Maria Teresa Virgilio, Antonella Festa, Agostino Galeone, Aldo De Rosa, Giuseppe Irace, Carlo Donadelli, Massimo Necas, Alois Amler, Evzen Tagliaferri, Pierosandro Tassone, Pierfrancesco Caraglia, Michele Mol Ther Nucleic Acids Article miR-125b, ubiquitously expressed and frequently dysregulated in several tumors, has gained special interest in the field of cancer research, displaying either oncogenic or oncosuppressor potential based on tumor type. We have previously demonstrated its tumor-suppressive role in multiple myeloma (MM), but the analysis of molecular mechanisms needs additional investigation. The purpose of this study was to explore the effects of miR-125b and its chemically modified analogs in modulating cell viability and cancer-associated molecular pathways, also focusing on the functional aspects of stress adaptation (autophagy and senescence), as well as programmed cell death (apoptosis). Based on the well-known low microRNA (miRNA) stability in therapeutic application, we designed chemically modified miR-125b mimics, laying the bases for their subsequent investigation in in vivo models. Our study clearly confirmed an oncosuppressive function depending on the repression of multiple targets, and it allowed the identification, for the first time, of miR-125b-dependent miR-34a stimulation as a possible consequence of the inhibitory role on the interleukin-6 receptor (IL-6R)/signal transducer and activator of transcription 3 (STAT3)/miR-34a feedback loop. Moreover, we identified a pattern of miR-125b-co-regulated miRNAs, shedding light on possible new players of anti-MM activity. Finally, functional studies also revealed a sequential activation of senescence, autophagy, and apoptosis, thus indicating, for the first two processes, an early cytoprotective and inhibitory role from apoptosis activation. American Society of Gene & Cell Therapy 2019-03-13 /pmc/articles/PMC6479071/ /pubmed/31009917 http://dx.doi.org/10.1016/j.omtn.2019.02.023 Text en © 2019 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Misso, Gabriella Zarone, Mayra Rachele Lombardi, Angela Grimaldi, Anna Cossu, Alessia Maria Ferri, Carmela Russo, Margherita Vuoso, Daniela Cristina Luce, Amalia Kawasaki, Hiromichi Di Martino, Maria Teresa Virgilio, Antonella Festa, Agostino Galeone, Aldo De Rosa, Giuseppe Irace, Carlo Donadelli, Massimo Necas, Alois Amler, Evzen Tagliaferri, Pierosandro Tassone, Pierfrancesco Caraglia, Michele miR-125b Upregulates miR-34a and Sequentially Activates Stress Adaption and Cell Death Mechanisms in Multiple Myeloma |
title | miR-125b Upregulates miR-34a and Sequentially Activates Stress Adaption and Cell Death Mechanisms in Multiple Myeloma |
title_full | miR-125b Upregulates miR-34a and Sequentially Activates Stress Adaption and Cell Death Mechanisms in Multiple Myeloma |
title_fullStr | miR-125b Upregulates miR-34a and Sequentially Activates Stress Adaption and Cell Death Mechanisms in Multiple Myeloma |
title_full_unstemmed | miR-125b Upregulates miR-34a and Sequentially Activates Stress Adaption and Cell Death Mechanisms in Multiple Myeloma |
title_short | miR-125b Upregulates miR-34a and Sequentially Activates Stress Adaption and Cell Death Mechanisms in Multiple Myeloma |
title_sort | mir-125b upregulates mir-34a and sequentially activates stress adaption and cell death mechanisms in multiple myeloma |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6479071/ https://www.ncbi.nlm.nih.gov/pubmed/31009917 http://dx.doi.org/10.1016/j.omtn.2019.02.023 |
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