Abstract 4482: MTAP regulates cell malignancy and is novel prognostic factor for kidney cancer

Abstract

Abstract Renal cell carcinoma (RCC), the 6th most common cancer in the US, is now considered a metabolic disease, which is increasing in incidence and demonstrates resistance usually within 2 years to all available therapies. Given that patients with metastatic RCC have unusually poor prognosis, it is urgent to discover potential molecules for predicting malignant changes that will lead to RCC. Herein, we have identified S-methyl- 5'-thioadenosine phosphorylase (MTAP) and its substrate methylthioadenosine (MTA) as a possible biomarker for early detection of RCC. In a screen of patients with RCC, we found that low MTAP expression is accompanied by high MTA level in RCC specimens, whereas concomitant high level of MTAP and low MTA abundance are detected in adjacent normal kidney tissues. Datasets for RCC (n=538) from The Cancer Genome Atlas (TCGA) showed that the patients with low MTAP levels have a significantly shorter overall survival as compared to the high MTAP group. Immunohistochemistry staining of normal kidney tissues confirmed an increase of MTAP protein expression compared to RCC tissues, and MTAP gene expression is inversely proportional to tumor grade. Accumulation of the metabolite MTA, a major substrate of MTAP, was observed in high-grade tumors showing high malignant potential. MTAP-knockout RCC cells displayed an elongated, spindle-like morphology with extended pseudopodial branches. Genetic manipulation of MTAP studies demonstrated that MTAP expression inhibits epithelial-mesenchymal transition, invasion and migration of RCC cells. Loss of MTAP resulted in an activation of IGF1R signaling in RCC cells. Taken together, our findings indicate a major contribution of MTAP loss to kidney cancer cell malignancy and provide a viable biomarker for tumor detections. Citation Format: Carissa Huang, Jihao Xu, Yichin Wu, Robert H. Weiss, Ching-Hsien Chen. MTAP regulates cell malignancy and is novel prognostic factor for kidney 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 4482.