Receptor-type tyrosine-protein phosphatase κ directly targets STAT3 activation for tumor suppression in nasal NK/T-cell lymphoma
| Autor: | Tianhuan Guo, Weiping Liu, Yun Wen Chen, Yuen Piu Chan, Eric Tse, Lijun Shen, Rex Au-Yeung, Yok-Lam Kwong, Gopesh Srivastava, KY Wong, Florence Loong, Johnny Cheuk On Tang, William W.L. Choi, Michelle L.Y. Wong, Gan Di Li, Norio Shimizu, Qian Tao |
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| Rok vydání: | 2015 |
| Předmět: |
Male
STAT3 Transcription Factor DNA Mutational Analysis Nose Neoplasms Immunology Phosphatase Down-Regulation Apoptosis Protein tyrosine phosphatase Biochemistry Cell Line Tumor Humans Neoplasm Invasiveness RNA Messenger RNA Neoplasm Phosphorylation Promoter Regions Genetic STAT3 Cell Proliferation Cell Nucleus biology Cell growth Tumor Suppressor Proteins Receptor-Like Protein Tyrosine Phosphatases Class 2 Cell Biology Hematology DNA Methylation Middle Aged Prognosis Natural killer T cell Molecular biology Lymphoma Extranodal NK-T-Cell Caspases Gene Knockdown Techniques DNA methylation Cancer research STAT protein biology.protein Female Gene Deletion Protein Binding |
| Zdroj: | Blood. 125:1589-1600 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2014-07-588970 |
| Popis: | Nasal-type natural killer/T-cell lymphoma (NKTCL) is an aggressive disease characterized by frequent deletions on 6q, and constitutive activation of signal transducer and activator of transcription 3 (STAT3). Phosphorylation at Tyr705 activates STAT3, inducing dimerization, nuclear translocation, and DNA binding. In this study, we investigated whether receptor-type tyrosine-protein phosphatase κ (PTPRK), the only protein tyrosine phosphatase at 6q that contains a STAT3-specifying motif, negatively regulates STAT3 activation in NKTCL. PTPRK was highly expressed in normal NK cells but was underexpressed in 4 of 5 (80%) NKTCL cell lines and 15 of 27 (55.6%) primary tumors. Significantly, PTPRK protein expression was inversely correlated with nuclear phospho-STAT3(Tyr705) expression in NKTCL cell lines (P = .025) and tumors (P = .040). PTPRK restoration decreased nuclear phospho-STAT3(Tyr705) levels, whereas knockdown of PTPRK increased such levels in NKTCL cells. Phosphatase substrate-trapping mutant assays demonstrated the binding of PTPRK to STAT3, and phosphatase assays showed that PTPRK directly dephosphorylated phospho-STAT3(Tyr705). Restoration of PTPRK inhibited tumor cell growth and reduced the migration and invasion ability of NKTCL cells. Monoallelic deletion and promoter hypermethylation caused underexpression of PTPRK messenger RNA in NKTCL, and methylation of the PTPRK promoter significantly correlated with inferior overall survival (P = .049) in NKTCL patients treated with the steroid-dexamethasone, methotrexate, ifosfamide, l-asparaginase, and etoposide regimen. Altogether, our findings show that PTPRK underexpression leads to STAT3 activation and contributes to NKTCL pathogenesis. |
| Databáze: | OpenAIRE |
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