Bioinformatic analysis of PTPRK reveals a potential link to STAT3 phosphorylation in HNSCC.

Purpose: The emerging role of various PTPRs (protein tyrosine phosphatase receptors) on signaling regulation prompted us to investigate the genomic alterations of members of the PTPR in HNSCC. PTPRK is a known tumor suppressor, and knockdown or mutation of PTPRK has been found to drive tumorigenesis in breast and colorectal cancer. The role of PTPRK in HNSCC is largely unknown. Recent genomic studies in HNSCC revealed that PTPRK is mutated in HNSCC. Here, we further investigated the genomic aberrations of PTPRK, in primary HNSCC tumors and examined if any of these genomic aberrations are associated with key phosphorylation changes in signaling proteins in HNSCC tumors. Experimental Design: Data-mining of the HNSCC genomic and protein array data was performed using the cBio portal (http://www.cbioportal.org/public-portal/). A total of 306 HNSCC primary tumors were analyzed in the genomic analysis, while proteomic data were available for a subset of these tumors (total of 200). We analyzed for genomic events, including PTPRK amplification, gain of copy number, and increased in mRNA expression (> 1 SD above the mean). The levels of phosphorylated signaling proteins of 150 proteins were compared between the PTPRK-altered group vs. the PTPRK-unaltered group. Preliminary validation on signaling changes were performed. Results: Bioinformatic analysis of the cBio data showed that PTPRK is mutated in 1% (2/200 cases), amplified in 0.5% (1/200 cases), with copy gain in 12% (24/200 cases), and increased mRNA expression in 13.5% (27/200 cases). There are no tumors with PTPRK deletion. These results implicate a gain of function of PTPRK in HNSCC. Unexpected proteomic findings revealed that increased phosphorylation of STAT3 (p = 0.005), ERBB2 (p = 0.018), and EGFR (p = 0.031) proteins were found to be associated with tumors with the genomic signature of “PTPRK-mutated/amplified/gain/increased in mRNA expression” vs. the PTPRK-unaltered tumors. Preliminary validation of the proteomic findings indicate that increased expression of PTPRK (by transient transfection into HNSCC cells) did result in increased pSTAT3 expression (34% increase vs. vector control). Discussion: This study used both bioinformatics and cellular assays to demonstrate PTPRK associated with enhanced pSTAT3. Future studies are required to elucidate the role of PTPRK, likely indirect, on STAT3 regulation. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A23. Citation Format: Kelsey P. Pendleton, Vivian W. Lui, Yiling Lu, Breean R. Gilbert, Kevin Levine, Gordon B. Mills, Jennifer R. Grandis. Bioinformatic analysis of PTPRK reveals a potential link to STAT3 phosphorylation in HNSCC. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A23.