Microenvironment regulates the expression of miR-21 and tumor suppressor genes PTEN, PIAS3 and PDCD4 through ZAP-70 in chronic lymphocytic leukemia
Carabia, Júlia (Vall d'Hebron Institut d'Oncologia)
Carpio Segura, Cecilia del Carmen (Vall d'Hebron Institut d'Oncologia)
Abrisqueta, Pau (Vall d'Hebron Institut d'Oncologia)
Jiménez, Isabel (Vall d'Hebron Institut d'Oncologia)
Purroy i Zuriguel, Noèlia (Vall d'Hebron Institut d'Oncologia)
Calpe, Eva (Vall d'Hebron Institut d'Oncologia)
Palacio-García, Carles (Vall d'Hebron Institut d'Oncologia)
Bosch Albareda, Francesc 1947- (Vall d'Hebron Institut d'Oncologia)
Crespo Maull, Marta (Vall d'Hebron Institut d'Oncologia)
Universitat Autònoma de Barcelona

Data:	2017
Resum:	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.
Ajuts:	Ministerio de Economía y Competitividad PI14/00055 Ministerio de Economía y Competitividad PI13/00279 Ministerio de Economía y Competitividad RYC-2012-12018
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Publicat a:	Scientific reports, Vol. 7 (september 2017) , ISSN 2045-2322

DOI: 10.1038/s41598-017-12135-7
PMID: 28947822

10 p, 3.1 MB

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