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Loss-of-Function PTPRD Mutations Lead to Increased STAT3 Activation and Sensitivity to STAT3 Inhibition in Head and Neck Cancer
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 gene...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4534317/ https://www.ncbi.nlm.nih.gov/pubmed/26267899 http://dx.doi.org/10.1371/journal.pone.0135750 |
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author | Peyser, Noah D. Du, Yu Li, Hua Lui, Vivian Xiao, Xiao Chan, Timothy A. Grandis, Jennifer R. |
author_facet | Peyser, Noah D. Du, Yu Li, Hua Lui, Vivian Xiao, Xiao Chan, Timothy A. Grandis, Jennifer R. |
author_sort | Peyser, Noah D. |
collection | PubMed |
description | 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 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. CONCLUSION: PTPRD mutation, but not methylation or copy number loss, may serve as a predictive biomarker of sensitivity to STAT3 inhibitors in HNSCC. |
format | Online Article Text |
id | pubmed-4534317 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-45343172015-08-24 Loss-of-Function PTPRD Mutations Lead to Increased STAT3 Activation and Sensitivity to STAT3 Inhibition in Head and Neck Cancer Peyser, Noah D. Du, Yu Li, Hua Lui, Vivian Xiao, Xiao Chan, Timothy A. Grandis, Jennifer R. PLoS One Research Article 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 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. CONCLUSION: PTPRD mutation, but not methylation or copy number loss, may serve as a predictive biomarker of sensitivity to STAT3 inhibitors in HNSCC. Public Library of Science 2015-08-12 /pmc/articles/PMC4534317/ /pubmed/26267899 http://dx.doi.org/10.1371/journal.pone.0135750 Text en © 2015 Peyser et al http://creativecommons.org/licenses/by/4.0/ 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 properly credited. |
spellingShingle | Research Article Peyser, Noah D. Du, Yu Li, Hua Lui, Vivian Xiao, Xiao Chan, Timothy A. Grandis, Jennifer R. Loss-of-Function PTPRD Mutations Lead to Increased STAT3 Activation and Sensitivity to STAT3 Inhibition in Head and Neck Cancer |
title | Loss-of-Function PTPRD Mutations Lead to Increased STAT3 Activation and Sensitivity to STAT3 Inhibition in Head and Neck Cancer |
title_full | Loss-of-Function PTPRD Mutations Lead to Increased STAT3 Activation and Sensitivity to STAT3 Inhibition in Head and Neck Cancer |
title_fullStr | Loss-of-Function PTPRD Mutations Lead to Increased STAT3 Activation and Sensitivity to STAT3 Inhibition in Head and Neck Cancer |
title_full_unstemmed | Loss-of-Function PTPRD Mutations Lead to Increased STAT3 Activation and Sensitivity to STAT3 Inhibition in Head and Neck Cancer |
title_short | Loss-of-Function PTPRD Mutations Lead to Increased STAT3 Activation and Sensitivity to STAT3 Inhibition in Head and Neck Cancer |
title_sort | loss-of-function ptprd mutations lead to increased stat3 activation and sensitivity to stat3 inhibition in head and neck cancer |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4534317/ https://www.ncbi.nlm.nih.gov/pubmed/26267899 http://dx.doi.org/10.1371/journal.pone.0135750 |
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