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Conference Paper: Epigenetic silencing of the receptor tyrosine phosphatase, PTPRK, located at the frequently deleted 6q22.33-q23.2 region, leads to tumor growth via the constitutive activation of STAT3 in nasal-type NK/T-cell lymphoma

TitleEpigenetic silencing of the receptor tyrosine phosphatase, PTPRK, located at the frequently deleted 6q22.33-q23.2 region, leads to tumor growth via the constitutive activation of STAT3 in nasal-type NK/T-cell lymphoma
Authors
Issue Date2011
PublisherAmerican Society of Hematology. The Journal's web site is located at http://bloodjournal.hematologylibrary.org/
Citation
The 53rd Annual Meeting and Exposition of the American Society of Hematology (ASH 2011), San Diego, CA., 10-13 December 2011. In Blood, 2011, v. 118 n. 21, abstract 1378 How to Cite?
AbstractTumorigenesis is a multi-step process and involves the silencing of tumor suppressor genes (TSGs) by genetic and/or epigenetic mechanisms. Aberrant hypermethylation of gene promoters is a major epigenetic mechanism associated with TSG silencing in cancer. To identify putative TSGs that might be epigenetically silenced in extranodal NK/T-cell lymphoma, nasal type (ENKL), a genome-wide screening was performed in a commonly deleted region 6q22.33-q23.2. PTPRK (protein tyrosine phosphatase, receptor type, kappa) was identified as the only gene out of 77 genes mapped to the 6q22.33-q23.2 region that was upregulated in four of five ENKL cell lines after treatment with the demethylation agent 5-aza-2' deoxycytidine (5-aza-dC). Further analysis by methylation-specific PCR (MSP) and bisulfite genomic sequencing (BGS) confirmed that the CpG island surrounding the transcriptional start site of PTPRK was methylated in ENKL cell lines not expressing PTPRK. Similarly, a significant correlation between methylation of the PTPRK promoter and downregulation of PTPRK mRNA and protein expression (p=0.019 and p=0.048, respectively) was detected in 39 primary ENKLs. PTPRK gene allelic loss was detected in 80% of cell lines and 47% of primary ENKLs. Functional analyses by in vitro assays showed that the re-expression of PTPRK by retroviral transduction in the PTPRK non-expressing NKYS cell line suppressed the size and number of colonies formed, led to a remarkable increase in the apoptotic cell population and cell cycle arrest at G0/G1 phase. Moreover, PTPRK re-expression substantially reduced the migration and invasion of NKYS cells. Conversely, the inhibitory effect of PTPRK was significantly decreased by partial shRNA knockdown of PTPRK expression in the PTPRK-expressing SNK-6 cell line. The re-expression of PTPRK in another PTPRK non-expressing YT cell line suppressed tumor growth and metastasis in a nude mouse xenograft model. Consistent with these in vitro and in vivo findings, clinicopathological correlation analysis showed that PTPRK silencing was detected mostly in the ENKL patients with advanced and metastatic disease. Examination of the PTPRK protein sequence revealed that the cytoplasmic domain possesses a consensus STAT3 binding domain (YXXQ). Re-expression of PTPRK in NKYS cells resulted in a significant decrease in the level of phospho-STAT3 (Tyr705), whereas PTPRK knockdown in SNK-6 cells resulted in an increased level of phospho-STAT3 (Tyr705). These data suggested that PTPRK dephosphorylates and regulates the oncoprotein STAT3. Overall, this study shows that PTPRK is a putative TSG in the 6q22.33-q23.2 region that is frequently deleted and epigenetically silenced in ENKL, and the loss of PTPRK expression promotes tumor growth via the aberrant constitutive activation of STAT3 in ENKL. Specific therapies aimed at targeting STAT3 warrants further exploration.
DescriptionOpen Access Journal
This journal issue is proceedings of ASH Conference 2011
Poster Sessions - 603. Oncogenes and Tumor Suppressors: Poster I
Persistent Identifierhttp://hdl.handle.net/10722/160323
ISSN
2014 Impact Factor: 10.452
2014 SCImago Journal Rankings: 5.246

 

DC FieldValueLanguage
dc.contributor.authorChen, YWen_US
dc.contributor.authorGuo, Ten_US
dc.contributor.authorShen, Len_US
dc.contributor.authorWong, KYen_US
dc.contributor.authorAu, WYen_US
dc.contributor.authorTao, Qen_US
dc.contributor.authorWong, LYen_US
dc.contributor.authorTang, COen_US
dc.contributor.authorChoi, WLen_US
dc.contributor.authorLiu, WPen_US
dc.contributor.authorLi, GDen_US
dc.contributor.authorShimizu, Nen_US
dc.contributor.authorTsuchiyama, Jen_US
dc.contributor.authorLoong, Fen_US
dc.contributor.authorLiang, Ren_US
dc.contributor.authorKwong, YLen_US
dc.contributor.authorSrivastava, Gen_US
dc.date.accessioned2012-08-16T06:08:00Z-
dc.date.available2012-08-16T06:08:00Z-
dc.date.issued2011en_US
dc.identifier.citationThe 53rd Annual Meeting and Exposition of the American Society of Hematology (ASH 2011), San Diego, CA., 10-13 December 2011. In Blood, 2011, v. 118 n. 21, abstract 1378en_US
dc.identifier.issn0006-4971-
dc.identifier.urihttp://hdl.handle.net/10722/160323-
dc.descriptionOpen Access Journal-
dc.descriptionThis journal issue is proceedings of ASH Conference 2011-
dc.descriptionPoster Sessions - 603. Oncogenes and Tumor Suppressors: Poster I-
dc.description.abstractTumorigenesis is a multi-step process and involves the silencing of tumor suppressor genes (TSGs) by genetic and/or epigenetic mechanisms. Aberrant hypermethylation of gene promoters is a major epigenetic mechanism associated with TSG silencing in cancer. To identify putative TSGs that might be epigenetically silenced in extranodal NK/T-cell lymphoma, nasal type (ENKL), a genome-wide screening was performed in a commonly deleted region 6q22.33-q23.2. PTPRK (protein tyrosine phosphatase, receptor type, kappa) was identified as the only gene out of 77 genes mapped to the 6q22.33-q23.2 region that was upregulated in four of five ENKL cell lines after treatment with the demethylation agent 5-aza-2' deoxycytidine (5-aza-dC). Further analysis by methylation-specific PCR (MSP) and bisulfite genomic sequencing (BGS) confirmed that the CpG island surrounding the transcriptional start site of PTPRK was methylated in ENKL cell lines not expressing PTPRK. Similarly, a significant correlation between methylation of the PTPRK promoter and downregulation of PTPRK mRNA and protein expression (p=0.019 and p=0.048, respectively) was detected in 39 primary ENKLs. PTPRK gene allelic loss was detected in 80% of cell lines and 47% of primary ENKLs. Functional analyses by in vitro assays showed that the re-expression of PTPRK by retroviral transduction in the PTPRK non-expressing NKYS cell line suppressed the size and number of colonies formed, led to a remarkable increase in the apoptotic cell population and cell cycle arrest at G0/G1 phase. Moreover, PTPRK re-expression substantially reduced the migration and invasion of NKYS cells. Conversely, the inhibitory effect of PTPRK was significantly decreased by partial shRNA knockdown of PTPRK expression in the PTPRK-expressing SNK-6 cell line. The re-expression of PTPRK in another PTPRK non-expressing YT cell line suppressed tumor growth and metastasis in a nude mouse xenograft model. Consistent with these in vitro and in vivo findings, clinicopathological correlation analysis showed that PTPRK silencing was detected mostly in the ENKL patients with advanced and metastatic disease. Examination of the PTPRK protein sequence revealed that the cytoplasmic domain possesses a consensus STAT3 binding domain (YXXQ). Re-expression of PTPRK in NKYS cells resulted in a significant decrease in the level of phospho-STAT3 (Tyr705), whereas PTPRK knockdown in SNK-6 cells resulted in an increased level of phospho-STAT3 (Tyr705). These data suggested that PTPRK dephosphorylates and regulates the oncoprotein STAT3. Overall, this study shows that PTPRK is a putative TSG in the 6q22.33-q23.2 region that is frequently deleted and epigenetically silenced in ENKL, and the loss of PTPRK expression promotes tumor growth via the aberrant constitutive activation of STAT3 in ENKL. Specific therapies aimed at targeting STAT3 warrants further exploration.-
dc.languageengen_US
dc.publisherAmerican Society of Hematology. The Journal's web site is located at http://bloodjournal.hematologylibrary.org/-
dc.relation.ispartofBlooden_US
dc.titleEpigenetic silencing of the receptor tyrosine phosphatase, PTPRK, located at the frequently deleted 6q22.33-q23.2 region, leads to tumor growth via the constitutive activation of STAT3 in nasal-type NK/T-cell lymphomaen_US
dc.typeConference_Paperen_US
dc.identifier.emailChen, YW: wywchen@hkucc.hku.hken_US
dc.identifier.emailGuo, T: huan95@yahoo.comen_US
dc.identifier.emailShen, L: lshen@graduate.hku.hken_US
dc.identifier.emailWong, KY: kywonga@hkucc.hku.hken_US
dc.identifier.emailAu, WY: auwing@hkucc.hku.hken_US
dc.identifier.emailWong, LY: mlywong@hkucc.hku.hken_US
dc.identifier.emailChoi, WL: choiwl@hkucc.hku.hken_US
dc.identifier.emailLoong, F: floong@hkucc.hku.hken_US
dc.identifier.emailLiang, R: rliang@hku.hken_US
dc.identifier.emailKwong, YL: ylkwong@hku.hken_US
dc.identifier.emailSrivastava, G: gopesh@pathology.hku.hk-
dc.identifier.authorityChoi, WL=rp00247en_US
dc.identifier.authorityLiang, R=rp00345en_US
dc.identifier.authorityKwong, YL=rp00358en_US
dc.identifier.authoritySrivastava, G=rp00365en_US
dc.description.naturelink_to_OA_fulltext-
dc.identifier.hkuros203851en_US
dc.identifier.volume118-
dc.identifier.issue21-
dc.publisher.placeUnited States-
dc.customcontrol.immutablesml 031326-

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