Abstract 4481: Tumor suppressive role of aquaglyceroporin-3 and PTPN13 in muscle invasive bladder cancer

Abstract

Abstract High mortality rates in bladder cancer (BCa) and lack of effective systemic therapies warrant identifying novel oncogenic pathways and therapeutic strategies. The cell-cell adhesion protein E-cadherin (Cdh1) is an important component of the transitional epithelium of the bladder wall, the cellular origin of most BCa. Cdh1 loss is crucial in epithelial-to-mesenchymal transition (EMT) and subsequent tumor metastasis in multiple cancers, including BCa. Cdh1 reportedly accumulates at cell junctions with the transmembrane aquaglyceroporin-3 channel (AQP3). Reports suggest that AQP3 expression is reduced in BCa of higher grade and stage. Although AQP3 has not been implicated in BCa metastasis, these observations led us to hypothesize that loss of AQP3 contributes to Cdh1 loss, thereby promoting EMT and systemic BCa invasion. Our previous data suggested that AQP3 expression is lower in higher grades of BCa cell lines. Reduced levels of Cdh1 and increased levels of Cdh1 repressors TWIST1, SNAIL1 and ZEB1 were noted in higher grade BCa cells. Our results indicate that AQP3 co-localizes with Cdh1 in lower grade BCa cell lines. This co-localization is not noted in higher grade BCa cells. Silencing of AQP3 by a specific siRNA in lower grade BCa cell lines resulted in reduced Cdh1 localization on the cell membrane. It remains to be deciphered if there is a physical association between Cdh1 and AQP3 and if reduced expression of AQP3 in higher grade BCa cell lines contributes to the loss of Cdh1 and thus facilitate increased EMT progression. Using tools at c-BioPortal to analyze The Cancer Genome Atlas (TCGA) BCa provisional dataset (n=413) revealed a direct correlation between AQP3 and tyrosine phosphatase PTPN13 expression, and similar to other cancers, PTPN13 deletion was associated with significantly reduced overall survival (p<0.04). It is known that PTPN13 negatively regulates Src activation. Furthermore, Src-mediated Cdh1 phosphorylation leading to Cdh1 degradation is known. We hypothesize that PTPN13 loss may promote BCa progression by increased Src-mediated Cdh1 phosphorylation resulting in Cdh1 degradation. Our data indicate that transcript and protein levels of PTPN13 are significantly lower in BCa cell lines derived from higher grade tumors relative to lower grade tumors. Silencing PTPN13 in low grade BCa cell lines significantly increased Src phosphorylation at Tyr416, the activation loop of the kinase domain. These results suggest that loss of PTPN13 in higher grade BCa cells result in increased Src-activation. PTPN13 has a novel tumor suppressive function in BCa: loss of PTPN13 results in sequential Src activation, Cdh1 degradation and increased EMT and metastatic potential of BCa cells. Further defining these mechanisms may help identify new strategies to effectively control BCa progression. Citation Format: Arpita A. Roy, Dinuka De Silva, Molly M. Lee, Donald P. Bottaro. Tumor suppressive role of aquaglyceroporin-3 and PTPN13 in muscle invasive bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4481.