| RRC ID |
66100
|
| 著者 |
Carabia J, Carpio C, Abrisqueta P, Jiménez I, Purroy N, Calpe E, Palacio C, Bosch F, Crespo M.
|
| タイトル |
Microenvironment regulates the expression of miR-21 and tumor suppressor genes PTEN, PIAS3 and PDCD4 through ZAP-70 in chronic lymphocytic leukemia.
|
| ジャーナル |
Sci Rep
|
| Abstract |
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.
|
| 巻・号 |
7(1)
|
| ページ |
12262
|
| 公開日 |
2017-9-25
|
| DOI |
10.1038/s41598-017-12135-7
|
| PII |
10.1038/s41598-017-12135-7
|
| PMID |
28947822
|
| PMC |
PMC5612928
|
| MeSH |
Apoptosis Regulatory Proteins / biosynthesis*
Cells, Cultured
Coculture Techniques
Gene Expression Regulation*
Gene Regulatory Networks
Humans
Leukemia, Lymphocytic, Chronic, B-Cell / pathology*
Leukocytes, Mononuclear / chemistry
MicroRNAs / biosynthesis*
Molecular Chaperones / biosynthesis*
PTEN Phosphohydrolase / biosynthesis*
Protein Inhibitors of Activated STAT / biosynthesis*
RNA-Binding Proteins / biosynthesis*
Signal Transduction
Tumor Microenvironment
ZAP-70 Protein-Tyrosine Kinase / biosynthesis*
|
| IF |
3.998
|
| リソース情報 |
| ヒト・動物細胞 |
UE6E7T-2(RCB2153) |
