The Experts below are selected from a list of 1554 Experts worldwide ranked by ideXlab platform
Nancy Choucair - One of the best experts on this subject based on the ideXlab platform.
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Evidence that homozygous PTPRD gene microdeletion causes trigonocephaly, hearing loss, and intellectual disability
Molecular Cytogenetics, 2015Co-Authors: Nancy Choucair, Cecile Mignon-ravix, Joelle Abou Ghoch, Ali Fawaz, Pierre Cacciagli, Laurent Villard, Andre Megarbane, Eliane ChoueryAbstract:Background: The premature fusion of metopic sutures results in the clinical phenotype of trigonocephaly. An association of this characteristic with the monosomy 9p syndrome is well established and the receptor-type protein tyrosine phosphatase gene (PTPRD), located in the 9p24.1p23 region and encoding a major component of the excitatory and inhibitory synaptic organization, is considered as a good candidate to be responsible for this form of craniosynostosis. Moreover PTPRD is known to recruit multiple postsynaptic partners such as IL1RAPL1 which gene alterations lead to non syndromic intellectual disability (ID). Results: We describe a 30 month old boy with severe intellectual disability, trigonocephaly and dysmorphic facial features such as a midface hypoplasia, a flat nose, a depressed nasal bridge, hypertelorism, a long philtrum and a drooping mouth. Microarray chromosomal analysis revealed the presence of a homozygous deletion involving the PTPRD gene, located on chromosome 9p22.3. Reverse Transcription PCR (RT- PCR) amplifications all along the gene failed to amplify the patient's cDNA in fibroblasts, indicating the presence of two null PTPRD alleles. Synaptic PTPRD interacts with IL1RAPL1 which defects have been associated with intellectual disability (ID) and autism spectrum disorder. The absence of the PTPRD transcript leads to a decrease in the expression of IL1RAPL1. These results suggest the direct involvement of PTPRD in ID, which is consistent with the PTPRD -/- mice phenotype. Deletions of PTPRD have been previously suggested as a cause of trigonocephaly in patients with monosomy 9p and genome-wide association study suggested variations in PTPRD are associated with hearing loss. Conclusions: The deletion identified in the reported patient supports previous hypotheses on its function in ID and hearing loss. However, its involvement in the occurrence of metopic synostosis is still to be discussed as more investigation of patients with the 9p monosomy syndrome is required.
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evidence that homozygous PTPRD gene microdeletion causes trigonocephaly hearing loss and intellectual disability
Molecular Cytogenetics, 2015Co-Authors: Nancy Choucair, Ali Fawaz, Pierre Cacciagli, Cecile Mignonravix, Joelle Abou Ghoch, Andre MegarbaneAbstract:Background The premature fusion of metopic sutures results in the clinical phenotype of trigonocephaly. An association of this characteristic with the monosomy 9p syndrome is well established and the receptor-type protein tyrosine phosphatase gene (PTPRD), located in the 9p24.1p23 region and encoding a major component of the excitatory and inhibitory synaptic organization, is considered as a good candidate to be responsible for this form of craniosynostosis. Moreover PTPRD is known to recruit multiple postsynaptic partners such as IL1RAPL1 which gene alterations lead to non syndromic intellectual disability (ID).
Armida W. M. Fabius - One of the best experts on this subject based on the ideXlab platform.
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Loss of the tyrosine phosphatase PTPRD leads to aberrant STAT3 activation and promotes gliomagenesis
Proceedings of the National Academy of Sciences of the United States of America, 2014Co-Authors: Berenice Ortiz, Armida W. M. Fabius, Alicia Pedraza, Cameron Brennan, Nikolaus Schultz, Kenneth L. Pitter, Jacqueline Bromberg, Jason T. Huse, Eric C. HollandAbstract:PTPRD, which encodes the protein tyrosine phosphatase receptor-δ, is one of the most frequently inactivated genes across human cancers, including glioblastoma multiforme (GBM). PTPRD undergoes both deletion and mutation in cancers, with copy number loss comprising the primary mode of inactivation in GBM. However, it is unknown whether loss of PTPRD promotes tumorigenesis in vivo, and the mechanistic basis of PTPRD function in tumors is unclear. Here, using genomic analysis and a glioma mouse model, we demonstrate that loss of PTPRD accelerates tumor formation and define the oncogenic context in which PTPRD loss acts. Specifically, we show that in human GBMs, heterozygous loss of PTPRD is the predominant type of lesion and that loss of PTPRD and the CDKN2A/p16INK4A tumor suppressor frequently co-occur. Accordingly, heterozygous loss of PTPRD cooperates with p16 deletion to drive gliomagenesis in mice. Moreover, loss of the PTPRD phosphatase resulted in phospho-Stat3 accumulation and constitutive activation of Stat3-driven genetic programs. Surprisingly, the consequences of PTPRD loss are maximal in the heterozygous state, demonstrating a tight dependence on gene dosage. PTPRD loss did not increase cell proliferation but rather altered pathways governing the macrophage response. In total, we reveal that PTPRD is a bona fide tumor suppressor, pinpoint PTPRD loss as a cause of aberrant STAT3 activation in gliomas, and establish PTPRD loss, in the setting of CDKN2A/p16INK4A deletion, as a driver of glioma progression.
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Protein tyrosine phosphatase receptor delta acts as a neuroblastoma tumor suppressor by destabilizing the aurora kinase a oncogene
Molecular Cancer, 2012Co-Authors: Maria Meehan, Berenice Ortiz, Laavanya Parthasarathi, Niamh Moran, Caroline A Jefferies, Niamh Foley, Elisa Lazzari, Derek Murphy, Jacqueline Ryan, Armida W. M. FabiusAbstract:Background Protein tyrosine phosphatase receptor delta (PTPRD) is a member of a large family of protein tyrosine phosphatases which negatively regulate tyrosine phosphorylation. Neuroblastoma is a major childhood cancer arising from precursor cells of the sympathetic nervous system which is known to acquire deletions and alterations in the expression patterns of PTPRD , indicating a potential tumor suppressor function for this gene. The molecular mechanism, however, by which PTPRD renders a tumor suppressor effect in neuroblastoma is unknown. Results As a molecular mechanism, we demonstrate that PTPRD interacts with aurora kinase A (AURKA), an oncogenic protein that is over-expressed in multiple forms of cancer, including neuroblastoma. Ectopic up-regulation of PTPRD in neuroblastoma dephosphorylates tyrosine residues in AURKA resulting in a destabilization of this protein culminating in interfering with one of AURKA's primary functions in neuroblastoma, the stabilization of MYCN protein, the gene of which is amplified in approximately 25 to 30% of high risk neuroblastoma. Conclusions PTPRD has a tumor suppressor function in neuroblastoma through AURKA dephosphorylation and destabilization and a downstream destabilization of MYCN protein, representing a novel mechanism for the function of PTPRD in neuroblastoma.
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Protein tyrosine phosphatase receptor delta acts as a neuroblastoma tumor suppressor by destabilizing the aurora kinase a oncogene.
Molecular cancer, 2012Co-Authors: Maria Meehan, Berenice Ortiz, Laavanya Parthasarathi, Niamh Moran, Caroline A Jefferies, Elisa Lazzari, Derek Murphy, Jacqueline Ryan, Niamh H. Foley, Armida W. M. FabiusAbstract:Background Protein tyrosine phosphatase receptor delta (PTPRD) is a member of a large family of protein tyrosine phosphatases which negatively regulate tyrosine phosphorylation. Neuroblastoma is a major childhood cancer arising from precursor cells of the sympathetic nervous system which is known to acquire deletions and alterations in the expression patterns of PTPRD, indicating a potential tumor suppressor function for this gene. The molecular mechanism, however, by which PTPRD renders a tumor suppressor effect in neuroblastoma is unknown.
Berenice Ortiz - One of the best experts on this subject based on the ideXlab platform.
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Deletion of PTPRD and Cdkn2a cooperate to accelerate tumorigenesis
2016Co-Authors: Berenice Ortiz, Julie R. White, Timothy A ChanAbstract:This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. PTPRD encodes the protein tyrosine phosphatase receptor type D and is frequently inactivated across many human cancers. Despite its frequent inactivation, it is unknown whether loss of PTPRD promotes tumorigenesis in vivo. PTPRD is located on chromosome 9p, as is CDKN2A, and the two loci are frequently deleted together. Here, we show that co-deletion of PTPRD and Cdkn2a cooperate to accelerate tumorigenesis. Interestingly, heterozygous loss of PTPRD was sufficient to promote tumorigenesis in our model, suggesting that PTPRD may be a haploinsufficient tumor suppressor. The loss of PTPRD resulted in changes to the tumor spectrum in mice and increased the frequency of lymphomas. In total, we reveal that PTPRD is a tumor suppressor that can promote tumorigenesis in concert with Cdkn2a loss
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Deletion of PTPRD and Cdkn2a cooperate to accelerate tumorigenesis.
Oncotarget, 2014Co-Authors: Berenice Ortiz, Julie R. White, Timothy A ChanAbstract:// Berenice Ortiz 1,2 , Julie R.White 3 , Wei H. Wu 2 and Timothy A. Chan 2,4,5 1 Gerstner Sloan-Kettering Graduate School, Memorial Sloan-Kettering Cancer Center, New York, NY, USA 2 Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA 3 The Tri-Institutional Laboratory of Comparative Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA 4 Dept. of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA 5 Brain Tumor Center, Memorial Sloan-Kettering Cancer Center, New York, New York, USA Correspondence: Timothy A. Chan, email: // Keywords : PTPRD, CDKN2A Received : May 9, 2014 Accepted : June 12, 2014 Published : June 14, 2014 Abstract PTPRD encodes the protein tyrosine phosphatase receptor type D and is frequently inactivated across many human cancers. Despite its frequent inactivation, it is unknown whether loss of PTPRD promotes tumorigenesis in vivo . PTPRD is located on chromosome 9p, as is CDKN2A , and the two loci are frequently deleted together. Here, we show that co-deletion of PTPRD and Cdkn2a cooperate to accelerate tumorigenesis. Interestingly,heterozygous loss of PTPRD was sufficient to promote tumorigenesis in our model, suggesting that PTPRD may be a haploinsufficient tumor suppressor. The loss of PTPRD resulted in changes to the tumor spectrum in mice and increased the frequency of lymphomas. In total, we reveal that PTPRD is a tumor suppressor that can promote tumorigenesis in concert with Cdkn2a loss.
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Loss of the tyrosine phosphatase PTPRD leads to aberrant STAT3 activation and promotes gliomagenesis
Proceedings of the National Academy of Sciences of the United States of America, 2014Co-Authors: Berenice Ortiz, Armida W. M. Fabius, Alicia Pedraza, Cameron Brennan, Nikolaus Schultz, Kenneth L. Pitter, Jacqueline Bromberg, Jason T. Huse, Eric C. HollandAbstract:PTPRD, which encodes the protein tyrosine phosphatase receptor-δ, is one of the most frequently inactivated genes across human cancers, including glioblastoma multiforme (GBM). PTPRD undergoes both deletion and mutation in cancers, with copy number loss comprising the primary mode of inactivation in GBM. However, it is unknown whether loss of PTPRD promotes tumorigenesis in vivo, and the mechanistic basis of PTPRD function in tumors is unclear. Here, using genomic analysis and a glioma mouse model, we demonstrate that loss of PTPRD accelerates tumor formation and define the oncogenic context in which PTPRD loss acts. Specifically, we show that in human GBMs, heterozygous loss of PTPRD is the predominant type of lesion and that loss of PTPRD and the CDKN2A/p16INK4A tumor suppressor frequently co-occur. Accordingly, heterozygous loss of PTPRD cooperates with p16 deletion to drive gliomagenesis in mice. Moreover, loss of the PTPRD phosphatase resulted in phospho-Stat3 accumulation and constitutive activation of Stat3-driven genetic programs. Surprisingly, the consequences of PTPRD loss are maximal in the heterozygous state, demonstrating a tight dependence on gene dosage. PTPRD loss did not increase cell proliferation but rather altered pathways governing the macrophage response. In total, we reveal that PTPRD is a bona fide tumor suppressor, pinpoint PTPRD loss as a cause of aberrant STAT3 activation in gliomas, and establish PTPRD loss, in the setting of CDKN2A/p16INK4A deletion, as a driver of glioma progression.
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Protein tyrosine phosphatase receptor delta acts as a neuroblastoma tumor suppressor by destabilizing the aurora kinase a oncogene
Molecular Cancer, 2012Co-Authors: Maria Meehan, Berenice Ortiz, Laavanya Parthasarathi, Niamh Moran, Caroline A Jefferies, Niamh Foley, Elisa Lazzari, Derek Murphy, Jacqueline Ryan, Armida W. M. FabiusAbstract:Background Protein tyrosine phosphatase receptor delta (PTPRD) is a member of a large family of protein tyrosine phosphatases which negatively regulate tyrosine phosphorylation. Neuroblastoma is a major childhood cancer arising from precursor cells of the sympathetic nervous system which is known to acquire deletions and alterations in the expression patterns of PTPRD , indicating a potential tumor suppressor function for this gene. The molecular mechanism, however, by which PTPRD renders a tumor suppressor effect in neuroblastoma is unknown. Results As a molecular mechanism, we demonstrate that PTPRD interacts with aurora kinase A (AURKA), an oncogenic protein that is over-expressed in multiple forms of cancer, including neuroblastoma. Ectopic up-regulation of PTPRD in neuroblastoma dephosphorylates tyrosine residues in AURKA resulting in a destabilization of this protein culminating in interfering with one of AURKA's primary functions in neuroblastoma, the stabilization of MYCN protein, the gene of which is amplified in approximately 25 to 30% of high risk neuroblastoma. Conclusions PTPRD has a tumor suppressor function in neuroblastoma through AURKA dephosphorylation and destabilization and a downstream destabilization of MYCN protein, representing a novel mechanism for the function of PTPRD in neuroblastoma.
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Protein tyrosine phosphatase receptor delta acts as a neuroblastoma tumor suppressor by destabilizing the aurora kinase a oncogene.
Molecular cancer, 2012Co-Authors: Maria Meehan, Berenice Ortiz, Laavanya Parthasarathi, Niamh Moran, Caroline A Jefferies, Elisa Lazzari, Derek Murphy, Jacqueline Ryan, Niamh H. Foley, Armida W. M. FabiusAbstract:Background Protein tyrosine phosphatase receptor delta (PTPRD) is a member of a large family of protein tyrosine phosphatases which negatively regulate tyrosine phosphorylation. Neuroblastoma is a major childhood cancer arising from precursor cells of the sympathetic nervous system which is known to acquire deletions and alterations in the expression patterns of PTPRD, indicating a potential tumor suppressor function for this gene. The molecular mechanism, however, by which PTPRD renders a tumor suppressor effect in neuroblastoma is unknown.
Timothy A Chan - One of the best experts on this subject based on the ideXlab platform.
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Deletion of PTPRD and Cdkn2a cooperate to accelerate tumorigenesis
2016Co-Authors: Berenice Ortiz, Julie R. White, Timothy A ChanAbstract:This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. PTPRD encodes the protein tyrosine phosphatase receptor type D and is frequently inactivated across many human cancers. Despite its frequent inactivation, it is unknown whether loss of PTPRD promotes tumorigenesis in vivo. PTPRD is located on chromosome 9p, as is CDKN2A, and the two loci are frequently deleted together. Here, we show that co-deletion of PTPRD and Cdkn2a cooperate to accelerate tumorigenesis. Interestingly, heterozygous loss of PTPRD was sufficient to promote tumorigenesis in our model, suggesting that PTPRD may be a haploinsufficient tumor suppressor. The loss of PTPRD resulted in changes to the tumor spectrum in mice and increased the frequency of lymphomas. In total, we reveal that PTPRD is a tumor suppressor that can promote tumorigenesis in concert with Cdkn2a loss
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loss of function PTPRD mutations lead to increased stat3 activation and sensitivity to stat3 inhibition in head and neck cancer
PLOS ONE, 2015Co-Authors: Nd Peyser, Vivian Wai Yan Lui, Xiao Xiao, Timothy A Chan, Jennifer R GrandisAbstract:© 2015 Peyser et al. Background Protein tyrosine phosphatase receptor type D (PTPRD) is a putative tumor suppressor in several cancers including head and neck squamous cell carcinoma (HNSCC). STAT3 is a frequently hyperactivated oncogene in HNSCC. As STAT3 is a direct substrate of PTPRD, we sought to determine the genetic or epigenetic alterations of PTPRD that contribute to overactive STAT3 in HNSCC. Methods We analyzed data from The Cancer Genome Atlas (TCGA) and our previous whole-exome sequencing study and summarized the mutation, methylation, and copy number status of PTPRD in HNSCC and other cancers. In vitro studies involved standard transfection and MTT protocols, as well as methylation-specific PCR. Results Our findings indicate that PTPRD mutation, rather thanmethylation or copy number alteration, is the primary mechanism by which PTPRD function is lost in HNSCC.We demonstrate that overexpression of wild-type PTPRD in HNSCC cells significantly inhibits growth and STAT3 activation while PTPRD mutants do not, suggesting thatmutation may lead to loss of function and subsequent hyper-phosphorylation of PTPRD substrates, especially STAT3. Importantly, we determined that HNSCC cells harboring an endogenous PTPRD mutation are more sensitive to STAT3 blockade than PTPRD wild-type cells.We additionally found that PTPRD mRNA expression does not correlate with pSTAT3 expression, suggesting that alterations that manifest through altered mRNA expression, including hypermethylation and gene copy number alterations, do not significantly contribute to STAT3 overactivation in HNSCC. Copyright:
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Loss-of-Function PTPRD Mutations Lead to Increased STAT3 Activation and Sensitivity to STAT3 Inhibition in Head and Neck Cancer
PloS one, 2015Co-Authors: Nd Peyser, Vivian Wai Yan Lui, Xiao Xiao, Timothy A Chan, Jennifer R GrandisAbstract:Protein tyrosine phosphatase receptor type D (PTPRD) is a putative tumor suppressor in several cancers including head and neck squamous cell carcinoma (HNSCC). STAT3 is a frequently hyperactivated oncogene in HNSCC. As STAT3 is a direct substrate of PTPRD, we sought to determine the genetic or epigenetic alterations of PTPRD that contribute to overactive STAT3 in HNSCC.We analyzed data from The Cancer Genome Atlas (TCGA) and our previous whole-exome sequencing study and summarized the mutation, methylation, and copy number status of PTPRD in HNSCC and other cancers. In vitro studies involved standard transfection and MTT protocols, as well as methylation-specific PCR.Our findings indicate that PTPRD mutation, rather than methylation or copy number alteration, is the primary mechanism by which PTPRD function is lost in HNSCC. We demonstrate that overexpression of wild-type PTPRD in HNSCC cells significantly inhibits growth and STAT3 activation while PTPRD mutants do not, suggesting that mutation may lead to loss of function and subsequent hyper-phosphorylation of PTPRD substrates, especially STAT3. Importantly, we determined that HNSCC cells harboring an endogenous PTPRD mutation are more sensitive to STAT3 blockade than PTPRD wild-type cells. We additionally found that PTPRD mRNA expression does not correlate with pSTAT3 expression, suggesting that alterations that manifest through altered mRNA expression, including hypermethylation and gene copy number alterations, do not significantly contribute to STAT3 overactivation in HNSCC.PTPRD mutation, but not methylation or copy number loss, may serve as a predictive biomarker of sensitivity to STAT3 inhibitors in HNSCC.
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PTPRD copy number alterations are frequent across cancers but are not associated with PTPRD mRNA expression in HNSCC.
2015Co-Authors: Nd Peyser, Xiao Xiao, Timothy A Chan, Vivian Lui, Jennifer R GrandisAbstract:(A) Copy number alteration of PTPRD in human cancers as determined by TCGA. (B) PTPRD copy number alterations do not correlate with altered PTPRD mRNA expression in HNSCC. A Jonckheere-Terpstra test was performed using StatXact software (Cytel, Cambridge, MA).
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Deletion of PTPRD and Cdkn2a cooperate to accelerate tumorigenesis.
Oncotarget, 2014Co-Authors: Berenice Ortiz, Julie R. White, Timothy A ChanAbstract:// Berenice Ortiz 1,2 , Julie R.White 3 , Wei H. Wu 2 and Timothy A. Chan 2,4,5 1 Gerstner Sloan-Kettering Graduate School, Memorial Sloan-Kettering Cancer Center, New York, NY, USA 2 Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA 3 The Tri-Institutional Laboratory of Comparative Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA 4 Dept. of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA 5 Brain Tumor Center, Memorial Sloan-Kettering Cancer Center, New York, New York, USA Correspondence: Timothy A. Chan, email: // Keywords : PTPRD, CDKN2A Received : May 9, 2014 Accepted : June 12, 2014 Published : June 14, 2014 Abstract PTPRD encodes the protein tyrosine phosphatase receptor type D and is frequently inactivated across many human cancers. Despite its frequent inactivation, it is unknown whether loss of PTPRD promotes tumorigenesis in vivo . PTPRD is located on chromosome 9p, as is CDKN2A , and the two loci are frequently deleted together. Here, we show that co-deletion of PTPRD and Cdkn2a cooperate to accelerate tumorigenesis. Interestingly,heterozygous loss of PTPRD was sufficient to promote tumorigenesis in our model, suggesting that PTPRD may be a haploinsufficient tumor suppressor. The loss of PTPRD resulted in changes to the tumor spectrum in mice and increased the frequency of lymphomas. In total, we reveal that PTPRD is a tumor suppressor that can promote tumorigenesis in concert with Cdkn2a loss.
Jennifer R Grandis - One of the best experts on this subject based on the ideXlab platform.
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loss of function PTPRD mutations lead to increased stat3 activation and sensitivity to stat3 inhibition in head and neck cancer
PLOS ONE, 2015Co-Authors: Nd Peyser, Vivian Wai Yan Lui, Xiao Xiao, Timothy A Chan, Jennifer R GrandisAbstract:© 2015 Peyser et al. Background Protein tyrosine phosphatase receptor type D (PTPRD) is a putative tumor suppressor in several cancers including head and neck squamous cell carcinoma (HNSCC). STAT3 is a frequently hyperactivated oncogene in HNSCC. As STAT3 is a direct substrate of PTPRD, we sought to determine the genetic or epigenetic alterations of PTPRD that contribute to overactive STAT3 in HNSCC. Methods We analyzed data from The Cancer Genome Atlas (TCGA) and our previous whole-exome sequencing study and summarized the mutation, methylation, and copy number status of PTPRD in HNSCC and other cancers. In vitro studies involved standard transfection and MTT protocols, as well as methylation-specific PCR. Results Our findings indicate that PTPRD mutation, rather thanmethylation or copy number alteration, is the primary mechanism by which PTPRD function is lost in HNSCC.We demonstrate that overexpression of wild-type PTPRD in HNSCC cells significantly inhibits growth and STAT3 activation while PTPRD mutants do not, suggesting thatmutation may lead to loss of function and subsequent hyper-phosphorylation of PTPRD substrates, especially STAT3. Importantly, we determined that HNSCC cells harboring an endogenous PTPRD mutation are more sensitive to STAT3 blockade than PTPRD wild-type cells.We additionally found that PTPRD mRNA expression does not correlate with pSTAT3 expression, suggesting that alterations that manifest through altered mRNA expression, including hypermethylation and gene copy number alterations, do not significantly contribute to STAT3 overactivation in HNSCC. Copyright:
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Loss-of-Function PTPRD Mutations Lead to Increased STAT3 Activation and Sensitivity to STAT3 Inhibition in Head and Neck Cancer
PloS one, 2015Co-Authors: Nd Peyser, Vivian Wai Yan Lui, Xiao Xiao, Timothy A Chan, Jennifer R GrandisAbstract:Protein tyrosine phosphatase receptor type D (PTPRD) is a putative tumor suppressor in several cancers including head and neck squamous cell carcinoma (HNSCC). STAT3 is a frequently hyperactivated oncogene in HNSCC. As STAT3 is a direct substrate of PTPRD, we sought to determine the genetic or epigenetic alterations of PTPRD that contribute to overactive STAT3 in HNSCC.We analyzed data from The Cancer Genome Atlas (TCGA) and our previous whole-exome sequencing study and summarized the mutation, methylation, and copy number status of PTPRD in HNSCC and other cancers. In vitro studies involved standard transfection and MTT protocols, as well as methylation-specific PCR.Our findings indicate that PTPRD mutation, rather than methylation or copy number alteration, is the primary mechanism by which PTPRD function is lost in HNSCC. We demonstrate that overexpression of wild-type PTPRD in HNSCC cells significantly inhibits growth and STAT3 activation while PTPRD mutants do not, suggesting that mutation may lead to loss of function and subsequent hyper-phosphorylation of PTPRD substrates, especially STAT3. Importantly, we determined that HNSCC cells harboring an endogenous PTPRD mutation are more sensitive to STAT3 blockade than PTPRD wild-type cells. We additionally found that PTPRD mRNA expression does not correlate with pSTAT3 expression, suggesting that alterations that manifest through altered mRNA expression, including hypermethylation and gene copy number alterations, do not significantly contribute to STAT3 overactivation in HNSCC.PTPRD mutation, but not methylation or copy number loss, may serve as a predictive biomarker of sensitivity to STAT3 inhibitors in HNSCC.
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PTPRD copy number alterations are frequent across cancers but are not associated with PTPRD mRNA expression in HNSCC.
2015Co-Authors: Nd Peyser, Xiao Xiao, Timothy A Chan, Vivian Lui, Jennifer R GrandisAbstract:(A) Copy number alteration of PTPRD in human cancers as determined by TCGA. (B) PTPRD copy number alterations do not correlate with altered PTPRD mRNA expression in HNSCC. A Jonckheere-Terpstra test was performed using StatXact software (Cytel, Cambridge, MA).
