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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2019-06-01
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| Series: | Molecular Therapy: Nucleic Acids |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S216225311930054X |
| _version_ | 1818932148577501184 |
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| author | Gabriella Misso Mayra Rachele Zarone Angela Lombardi Anna Grimaldi Alessia Maria Cossu Carmela Ferri Margherita Russo Daniela Cristina Vuoso Amalia Luce Hiromichi Kawasaki Maria Teresa Di Martino Antonella Virgilio Agostino Festa Aldo Galeone Giuseppe De Rosa Carlo Irace Massimo Donadelli Alois Necas Evzen Amler Pierosandro Tagliaferri Pierfrancesco Tassone Michele Caraglia |
| author_facet | Gabriella Misso Mayra Rachele Zarone Angela Lombardi Anna Grimaldi Alessia Maria Cossu Carmela Ferri Margherita Russo Daniela Cristina Vuoso Amalia Luce Hiromichi Kawasaki Maria Teresa Di Martino Antonella Virgilio Agostino Festa Aldo Galeone Giuseppe De Rosa Carlo Irace Massimo Donadelli Alois Necas Evzen Amler Pierosandro Tagliaferri Pierfrancesco Tassone Michele Caraglia |
| author_sort | Gabriella Misso |
| collection | DOAJ |
| 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. Keywords: miR-125b, multiple myeloma, apoptosis, autophagy, senescence, miRNome, miRNA therapeutics, miR-34a, next generation sequencing, signal transduction |
| first_indexed | 2024-12-20T04:27:53Z |
| format | Article |
| id | doaj.art-43ab1c060b9e4d41bafb080a8b2d16e6 |
| institution | Directory Open Access Journal |
| issn | 2162-2531 |
| language | English |
| last_indexed | 2024-12-20T04:27:53Z |
| publishDate | 2019-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj.art-43ab1c060b9e4d41bafb080a8b2d16e62022-12-21T19:53:27ZengElsevierMolecular Therapy: Nucleic Acids2162-25312019-06-0116391406miR-125b Upregulates miR-34a and Sequentially Activates Stress Adaption and Cell Death Mechanisms in Multiple MyelomaGabriella Misso0Mayra Rachele Zarone1Angela Lombardi2Anna Grimaldi3Alessia Maria Cossu4Carmela Ferri5Margherita Russo6Daniela Cristina Vuoso7Amalia Luce8Hiromichi Kawasaki9Maria Teresa Di Martino10Antonella Virgilio11Agostino Festa12Aldo Galeone13Giuseppe De Rosa14Carlo Irace15Massimo Donadelli16Alois Necas17Evzen Amler18Pierosandro Tagliaferri19Pierfrancesco Tassone20Michele Caraglia21Department of Precision Medicine, University of Campania “Luigi Vanvitelli,” 80138 Naples, Italy; Corresponding author: Gabriella Misso, Department of Precision Medicine, University of Campania “Luigi Vanvitelli,” 80138 Naples, Italy.Department of Precision Medicine, University of Campania “Luigi Vanvitelli,” 80138 Naples, ItalyDepartment of Precision Medicine, University of Campania “Luigi Vanvitelli,” 80138 Naples, ItalyDepartment of Precision Medicine, University of Campania “Luigi Vanvitelli,” 80138 Naples, ItalyDepartment of Precision Medicine, University of Campania “Luigi Vanvitelli,” 80138 Naples, Italy; IRGS, Biogem, Molecular and Precision Oncology Laboratory, Via Camporeale, 83031 Ariano Irpino, ItalyDepartment of Precision Medicine, University of Campania “Luigi Vanvitelli,” 80138 Naples, ItalyDepartment of Precision Medicine, University of Campania “Luigi Vanvitelli,” 80138 Naples, ItalyDepartment of Precision Medicine, University of Campania “Luigi Vanvitelli,” 80138 Naples, ItalyDepartment of Precision Medicine, University of Campania “Luigi Vanvitelli,” 80138 Naples, ItalyDrug Discovery Laboratory, Wakunaga Pharmaceutical Co., Ltd., Hiroshima, JapanDepartment of Experimental and Clinical Medicine, University Magna Græcia of Catanzaro, Salvatore Venuta University Campus, 88100 Catanzaro, Italy; Corresponding author: Maria Teresa Di Martino, Medical Oncology Unit, Department of Experimental and Clinical Medicine, University Magna Græcia of Catanzaro, Salvatore Venuta University Campus, 88100 Catanzaro, Italy.Department of Pharmacy, School of Medicine, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, ItalyDepartment of Precision Medicine, University of Campania “Luigi Vanvitelli,” 80138 Naples, ItalyDepartment of Pharmacy, School of Medicine, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, ItalyDepartment of Pharmacy, School of Medicine, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, ItalyDepartment of Pharmacy, School of Medicine, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, ItalyDepartment of Neurosciences, Biomedicine and Movement Sciences, Section of Biochemistry, University of Verona, Verona, ItalyCEITEC – Central European Institute of Technology, University of Veterinary and Pharmaceutical Sciences Brno, Brno, Czech RepublicSecond Medical Faculty, Charles University in Prague, Prague, Czech RepublicDepartment of Experimental and Clinical Medicine, University Magna Græcia of Catanzaro, Salvatore Venuta University Campus, 88100 Catanzaro, ItalyDepartment of Experimental and Clinical Medicine, University Magna Græcia of Catanzaro, Salvatore Venuta University Campus, 88100 Catanzaro, ItalyDepartment of Precision Medicine, University of Campania “Luigi Vanvitelli,” 80138 Naples, Italy; IRGS, Biogem, Molecular and Precision Oncology Laboratory, Via Camporeale, 83031 Ariano Irpino, Italy; Corresponding author: Michele Caraglia, Department of Precision Medicine, University of Campania “Luigi Vanvitelli,” 80138 Naples, Italy.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. Keywords: miR-125b, multiple myeloma, apoptosis, autophagy, senescence, miRNome, miRNA therapeutics, miR-34a, next generation sequencing, signal transductionhttp://www.sciencedirect.com/science/article/pii/S216225311930054X |
| spellingShingle | Gabriella Misso Mayra Rachele Zarone Angela Lombardi Anna Grimaldi Alessia Maria Cossu Carmela Ferri Margherita Russo Daniela Cristina Vuoso Amalia Luce Hiromichi Kawasaki Maria Teresa Di Martino Antonella Virgilio Agostino Festa Aldo Galeone Giuseppe De Rosa Carlo Irace Massimo Donadelli Alois Necas Evzen Amler Pierosandro Tagliaferri Pierfrancesco Tassone Michele Caraglia miR-125b Upregulates miR-34a and Sequentially Activates Stress Adaption and Cell Death Mechanisms in Multiple Myeloma Molecular Therapy: Nucleic Acids |
| 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 |
| url | http://www.sciencedirect.com/science/article/pii/S216225311930054X |
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