title: Receptor-type tyrosine-protein phosphatase κ directly targets STAT3 activation for tumor suppression in nasal NK/T-cell lymphoma.
abstract: 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.
authors.affiliation: Lymphoma Research Laboratory, Department of Pathology, Queen Mary Hospital, The University of Hong Kong, Hong Kong;
authors.forename: Yun-Wen
authors.initials: YW
authors.lastname: Chen
authors.affiliation: Lymphoma Research Laboratory, Department of Pathology, Queen Mary Hospital, The University of Hong Kong, Hong Kong;
authors.forename: Tianhuan
authors.initials: T
authors.lastname: Guo
authors.affiliation: Lymphoma Research Laboratory, Department of Pathology, Queen Mary Hospital, The University of Hong Kong, Hong Kong;
authors.forename: Lijun
authors.initials: L
authors.lastname: Shen
authors.affiliation: Lymphoma Research Laboratory, Department of Pathology, Queen Mary Hospital, The University of Hong Kong, Hong Kong;
authors.forename: Kai-Yau
authors.initials: KY
authors.lastname: Wong
authors.affiliation: Cancer Epigenetics Laboratory, Department of Clinical Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong;
authors.forename: Qian
authors.initials: Q
authors.lastname: Tao
authors.affiliation: Lymphoma Research Laboratory, Department of Pathology, Queen Mary Hospital, The University of Hong Kong, Hong Kong;
authors.forename: William W L
authors.initials: WW
authors.lastname: Choi
authors.affiliation: Lymphoma Research Laboratory, Department of Pathology, Queen Mary Hospital, The University of Hong Kong, Hong Kong;
authors.forename: Rex K H
authors.initials: RK
authors.lastname: Au-Yeung
authors.affiliation: Lymphoma Research Laboratory, Department of Pathology, Queen Mary Hospital, The University of Hong Kong, Hong Kong;
authors.forename: Yuen-Piu
authors.initials: YP
authors.lastname: Chan
authors.affiliation: Lymphoma Research Laboratory, Department of Pathology, Queen Mary Hospital, The University of Hong Kong, Hong Kong;
authors.forename: Michelle L Y
authors.initials: ML
authors.lastname: Wong
authors.affiliation: Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong;
authors.forename: Johnny C O
authors.initials: JC
authors.lastname: Tang
authors.affiliation: Department of Pathology, West-China Hospital of Sichuan University, Chengdu, Sichuan, China;
authors.forename: Wei-Ping
authors.initials: WP
authors.lastname: Liu
authors.affiliation: Department of Pathology, West-China Hospital of Sichuan University, Chengdu, Sichuan, China;
authors.forename: Gan-Di
authors.initials: GD
authors.lastname: Li
authors.affiliation: Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan; and.
authors.forename: Norio
authors.initials: N
authors.lastname: Shimizu
authors.affiliation: Lymphoma Research Laboratory, Department of Pathology, Queen Mary Hospital, The University of Hong Kong, Hong Kong;
authors.forename: Florence
authors.initials: F
authors.lastname: Loong
authors.affiliation: Division of Hematology, Medical Oncology and Bone Marrow Transplantation, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong.
authors.forename: Eric
authors.initials: E
authors.lastname: Tse
authors.affiliation: Division of Hematology, Medical Oncology and Bone Marrow Transplantation, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong.
authors.forename: Yok-Lam
authors.initials: YL
authors.lastname: Kwong
authors.affiliation: Lymphoma Research Laboratory, Department of Pathology, Queen Mary Hospital, The University of Hong Kong, Hong Kong;
authors.forename: Gopesh
authors.initials: G
authors.lastname: Srivastava
mesh_terms: D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D015536:Down-Regulation; D005260:Female; D017353:Gene Deletion; D055785:Gene Knockdown Techniques; D006801:Humans; D054391:Lymphoma, Extranodal NK-T-Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009669:Nose Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D011379:Prognosis; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000737:chemistry / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; D012334:RNA, Neoplasm; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D025521:Tumor Suppressor Proteins; C489852:PTPRK protein, human; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2; D020169:Caspases