Loss-of-function PTPRD mutations lead to increased STAT3 activation and sensitivity to STAT3 inhibition in head and neck cancer

Peyser, ND and Du, Y and Li, H and Lui, V and Xiao, X and Chan, TA and Grandis, JR (2015) Loss-of-function PTPRD mutations lead to increased STAT3 activation and sensitivity to STAT3 inhibition in head and neck cancer. PLoS ONE, 10 (8).

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Abstract

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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Details

Item Type:	Article
Status:	Published
Creators/Authors:	Creators Email Pitt Username ORCID Peyser, ND nop4@pitt.edu NOP4 Du, Y Li, H Lui, V Xiao, X Chan, TA Grandis, JR
Contributors:	Contribution Contributors Name Email Pitt Username ORCID Editor Tao, Qian UNSPECIFIED UNSPECIFIED UNSPECIFIED
Date:	12 August 2015
Date Type:	Publication
Access Restriction:	No restriction; Release the ETD for access worldwide immediately.
Journal or Publication Title:	PLoS ONE
Volume:	10
Number:	8
DOI or Unique Handle:	10.1371/journal.pone.0135750
Institution:	University of Pittsburgh
Schools and Programs:	School of Medicine > Otolaryngology School of Medicine > Pharmacology and Chemical Biology
Refereed:	Yes
Date Deposited:	23 Aug 2016 14:28
Last Modified:	30 Mar 2021 13:56
URI:	http://d-scholarship.pitt.edu/id/eprint/28397

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