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Article: Receptor-type tyrosine-protein phosphatase κ directly targets STAT3 activation for tumor suppression in nasal NK/T-cell lymphoma

TitleReceptor-type tyrosine-protein phosphatase κ directly targets STAT3 activation for tumor suppression in nasal NK/T-cell lymphoma
Authors
Issue Date2015
PublisherAmerican Society of Hematology. The Journal's web site is located at http://bloodjournal.hematologylibrary.org/
Citation
Blood, 2015, v. 125 n. 10, p. 1589-1600 How to Cite?
AbstractNasal-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.
Persistent Identifierhttp://hdl.handle.net/10722/211035
ISSN
2015 Impact Factor: 11.841
2015 SCImago Journal Rankings: 6.395

 

DC FieldValueLanguage
dc.contributor.authorChen, WYW-
dc.contributor.authorGuo, T-
dc.contributor.authorShen, L-
dc.contributor.authorWong, KY-
dc.contributor.authorTao, Q-
dc.contributor.authorChoi, WL-
dc.contributor.authorAu Yeung, KHR-
dc.contributor.authorChan, YP-
dc.contributor.authorWong, MLY-
dc.contributor.authorTang, JCO-
dc.contributor.authorLiu, WP-
dc.contributor.authorLi, GD-
dc.contributor.authorShimizu, N-
dc.contributor.authorLoong, F-
dc.contributor.authorTse, EWC-
dc.contributor.authorKwong, YL-
dc.contributor.authorSrivastava, G-
dc.date.accessioned2015-07-03T04:39:05Z-
dc.date.available2015-07-03T04:39:05Z-
dc.date.issued2015-
dc.identifier.citationBlood, 2015, v. 125 n. 10, p. 1589-1600-
dc.identifier.issn0006-4971-
dc.identifier.urihttp://hdl.handle.net/10722/211035-
dc.description.abstractNasal-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.-
dc.languageeng-
dc.publisherAmerican Society of Hematology. The Journal's web site is located at http://bloodjournal.hematologylibrary.org/-
dc.relation.ispartofBlood-
dc.rightsThis research was originally published in The Hematologist: ASH News and Reports. Author(s). Title. The Hematologist: ASH News and Reports. Year;Vol,Issue:pp-pp. © the American Society of Hematology.-
dc.titleReceptor-type tyrosine-protein phosphatase κ directly targets STAT3 activation for tumor suppression in nasal NK/T-cell lymphoma-
dc.typeArticle-
dc.identifier.emailChen, WYW: wywchen@HKUCC-COM.hku.hk-
dc.identifier.emailWong, KY: kai@pathology.hku.hk-
dc.identifier.emailChoi, WL: wlchoi@pathology.hku.hk-
dc.identifier.emailAu Yeung, KHR: rex.auyeung@hku.hk-
dc.identifier.emailWong, MLY: mlywong@hkucc.hku.hk-
dc.identifier.emailTang, JCO: cotang@hkucc.hku.hk-
dc.identifier.emailLoong, F: floong@hkucc.hku.hk-
dc.identifier.emailTse, EWC: ewctse@hku.hk-
dc.identifier.emailKwong, YL: ylkwong@hkucc.hku.hk-
dc.identifier.emailSrivastava, G: gopesh@pathology.hku.hk-
dc.identifier.authorityChoi, WL=rp00247-
dc.identifier.authorityAu Yeung, KHR=rp01877-
dc.identifier.authorityTse, EWC=rp00471-
dc.identifier.authorityKwong, YL=rp00358-
dc.identifier.authoritySrivastava, G=rp00365-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1182/blood-2014-07-588970-
dc.identifier.pmid25612622-
dc.identifier.hkuros244318-
dc.identifier.volume125-
dc.identifier.issue10-
dc.identifier.spage1589-
dc.identifier.epage1600-
dc.publisher.placeUnited States-

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