title: NPM-ALK up-regulates iNOS expression through a STAT3/microRNA-26a-dependent mechanism.
abstract: 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.
authors: Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Haifeng
authors: H
authors: Zhu
authors: Deeksha
authors: D
authors: Vishwamitra
authors: Choladda V
authors: CV
authors: Curry
authors: Roxsan
authors: R
authors: Manshouri
authors: Lixia
authors: L
authors: Diao
authors: Aarish
authors: A
authors: Khan
authors: Hesham M
authors: HM
authors: Amin
mesh_terms: D002448:Cell Adhesion / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D015536:Down-Regulation / Q000235:genetics / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D007097:Imines / Q000494:pharmacology; D016399:Lymphoma, T-Cell / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000235:genetics; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology
chemical_list: D007097:Imines; D035683:MicroRNAs; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D011505:Protein-Tyrosine Kinases; D050796:STAT3 Transcription Factor; D025521:Tumor Suppressor Proteins; D014443:Tyrosine; C486483:CTDSPL protein, human; C528163:MIRN26 microRNA, human; C496401:N-((3-(aminomethyl)phenyl)methyl)ethanimidamide; C494086:STAT3 protein, human; C002744:3-nitrotyrosine; C496319:NOS2 protein, human; C107023:p80(NPM-ALK) protein