Microenvironment regulates the expression of miR-21 and tumor suppressor genes PTEN, PIAS3 and PDCD4 through ZAP-70 in chronic lymphocytic leukemia
| Autor: | Carabia, Júlia, Carpio Segura, Cecilia del Carmen, Abrisqueta, Pau, Jiménez, Isabel, Purroy i Zuriguel, Noèlia, Calpe, Eva, Palacio-García, Carles, Bosch José, Francesc Xavier, Crespo, Marta, Universitat Autònoma de Barcelona |
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| Přispěvatelé: | UAM. Departamento de Física Aplicada |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Microenvironment MicroRNA-21 Tumor suppressor genes Medicina Chronic lymphocytic leukemia lcsh:Medicine chemical and pharmacologic phenomena Biology Article 03 medical and health sciences Downregulation and upregulation hemic and lymphatic diseases Tumor Microenvironment medicine Humans PTEN Gene Regulatory Networks lcsh:Science Cells Cultured Tumor microenvironment ZAP-70 Protein-Tyrosine Kinase Multidisciplinary lcsh:R PTEN Phosphohydrolase breakpoint cluster region RNA-Binding Proteins hemic and immune systems BCR Signaling Pathway medicine.disease Leukemia Lymphocytic Chronic B-Cell Protein Inhibitors of Activated STAT Coculture Techniques Cell biology MicroRNAs Lymphocytic leukemia Leukemia 030104 developmental biology Gene Expression Regulation Leukocytes Mononuclear Cancer research biology.protein lcsh:Q Ectopic expression Apoptosis Regulatory Proteins Molecular Chaperones Signal Transduction |
| Zdroj: | Biblos-e Archivo. Repositorio Institucional de la UAM instname Scientific Reports, Vol 7, Iss 1, Pp 1-10 (2017) Scientific Reports Dipòsit Digital de Documents de la UAB Universitat Autònoma de Barcelona |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/s41598-017-12135-7 |
| Popis: | Chronic lymphocytic leukemia (CLL) cells are highly dependent on microenvironment, being the BCR pathway one key player in this crosstalk. Among proteins participating, ZAP-70 enhances response to microenvironmental stimuli. MicroRNA-21 (miR-21) is overexpressed in diverse neoplasias including CLL, where it has been associated to refractoriness to fludarabine and to shorter time to progression and survival. To further elucidate the role of ZAP-70 in the biology of CLL, we studied its involvement in miR-21 regulation. MiR-21 expression was higher in CLL cells with high ZAP-70. Ectopic expression of ZAP-70 induced transcription of miR-21 via MAPK and STAT3, which subsequently induced downregulation of tumor suppressors targeted by miR-21. The co-culture of primary CLL cells mimicking the microenvironment induced ZAP-70 and miR-21 expression, as well as downregulation of miR-21 targets. Interestingly, the increase in miR-21 after co-culture was significantly impaired by ibrutinib, indicating that the BCR signaling pathway is involved in its regulation. Finally, survival of CLL cells induced by the co-culture correlated with miR-21 upregulation. In conclusion, stimuli from the microenvironment regulate miR-21 and its targeted tumor suppressor genes via a signaling pathway involving ZAP-70, thus contributing to the cytoprotection offered by the microenvironment particularly observed in CLL cells expressing ZAP-70. This work was supported by research funding from the Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias (PI14/00055, F.B. and PI13/00279, M.C.), cofinanced by the European Regional Development Fund (ERDF) and Asociación Española Contra el Cáncer (AECC Barcelona, M.C. and P.A.). M.C. holds a contract from Ministerio de Economía y Competitividad (MINECO) (RYC-2012-12018). Authors thank the Cellex Foundation for providing research facilities and equipment |
| Databáze: | OpenAIRE |
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