Document Detail

NPM-ALK up-regulates iNOS expression through a STAT3/microRNA-26a-dependent mechanism.
MedLine Citation:
PMID:  23338972     Owner:  NLM     Status:  MEDLINE    
NPM-ALK chimeric oncogene is aberrantly expressed in an aggressive subset of T-cell lymphomas that frequently occurs in children and young adults. The mechanisms underlying the oncogenic effects of NPM-ALK are not completely elucidated. Inducible nitric oxide synthase (iNOS) promotes the survival and maintains the malignant phenotype of cancer cells by generating NO, a highly active free radical. We tested the hypothesis that iNOS is deregulated in NPM-ALK(+) T-cell lymphoma and promotes the survival of this lymphoma. In line with this possibility, an iNOS inhibitor and NO scavenger decreased the viability, adhesion, and migration of NPM-ALK(+) T-cell lymphoma cells, and an NO donor reversed these effects. Moreover, the NO donor salvaged the viability of lymphoma cells treated with ALK inhibitors. In further support of an important role of iNOS, we found iNOS protein to be highly expressed in NPM-ALK(+) T-cell lymphoma cell lines and in 79% of primary tumours but not in human T lymphocytes. Although expression of iNOS mRNA was identified in NPM-ALK(+) T-cell lymphoma cell lines and tumours, iNOS mRNA was remarkably elevated in T lymphocytes, suggesting post-transcriptional regulation. Consistently, we found that miR-26a contains potential binding sites and interacts with the 3'-UTR of iNOS. In addition, miR-26a was significantly decreased in NPM-ALK(+) T-cell lymphoma cell lines and tumours compared with T lymphocytes and reactive lymph nodes. Restoration of miR-26a in lymphoma cells abrogated iNOS protein expression and decreased NO production and cell viability, adhesion, and migration. Importantly, the effects of miR-26a were substantially attenuated when the NO donor was simultaneously used to treat lymphoma cells. Our investigation of the mechanisms underlying the decrease in miR-26a in this lymphoma revealed novel evidence that STAT3, a major downstream substrate of NPM-ALK tyrosine kinase activity, suppresses MIR26A1 gene expression.
Haifeng Zhu; Deeksha Vishwamitra; Choladda V Curry; Roxsan Manshouri; Lixia Diao; Aarish Khan; Hesham M Amin
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-03-14
Journal Detail:
Title:  The Journal of pathology     Volume:  230     ISSN:  1096-9896     ISO Abbreviation:  J. Pathol.     Publication Date:  2013 May 
Date Detail:
Created Date:  2013-04-11     Completed Date:  2013-06-13     Revised Date:  2014-05-07    
Medline Journal Info:
Nlm Unique ID:  0204634     Medline TA:  J Pathol     Country:  England    
Other Details:
Languages:  eng     Pagination:  82-94     Citation Subset:  IM    
Copyright Information:
Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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MeSH Terms
Cell Adhesion / physiology
Cell Line, Tumor
Cell Movement / physiology
Cell Survival / physiology
Down-Regulation / genetics,  physiology
Gene Expression Regulation, Neoplastic / physiology
Imines / pharmacology
Lymphoma, T-Cell / genetics*,  metabolism*,  pathology
MicroRNAs / genetics,  metabolism*
Nitric Oxide / metabolism
Nitric Oxide Synthase Type II / antagonists & inhibitors,  genetics*,  metabolism
Protein-Tyrosine Kinases / genetics,  metabolism*
STAT3 Transcription Factor / genetics,  metabolism*
Signal Transduction / genetics,  physiology
Tumor Suppressor Proteins / genetics
Tyrosine / analogs & derivatives,  metabolism
Up-Regulation / genetics,  physiology
Grant Support
Reg. No./Substance:
0/CTDSPL protein, human; 0/Imines; 0/MIRN26A microRNA, human; 0/MicroRNAs; 0/N-((3-(aminomethyl)phenyl)methyl)ethanimidamide; 0/STAT3 Transcription Factor; 0/STAT3 protein, human; 0/Tumor Suppressor Proteins; 31C4KY9ESH/Nitric Oxide; 3604-79-3/3-nitrotyrosine; 42HK56048U/Tyrosine; EC protein, human; EC Oxide Synthase Type II; EC 2.7.1.-/p80(NPM-ALK) protein; EC Kinases

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