Abstract 1494: Characterization of a novel pro-tumorigenic TGF-β RII mutation from oral squamous cell carcinoma

Abstract

Abstract TGF-β signaling plays various roles in tumor progression. Tumor suppressive TGF- β signaling is involved in early steps of carcinogenesis through loss of function which leads to deregulated proliferation. On the contrary, TGF- β signaling could be pro-tumorigenic in later stages of carcinogenesis by promoting epithelial-mesenchymal transition (EMT). Most of the reported TGF- β receptor-II mutations were loss of tumor suppressor function mutations and no pro-tumorigenic TGF- β receptor-II mutation has been identified in human tumors. This study aimed to analyze a novel mutation of TGF- β receptor-II found in metastatic lymph node of oral squamous cell carcinoma. This mutant converts amino acid 227 from I to T and amino acid 236 from N to D of TGF- β receptor-II. Promoter assay using 3TP-lux reporter showed that 227/236 double mutation significantly increased both basal and TGF- β-induced luciferase activity as compared to wild type in DR-26, TGF- β receptor-II-defective mink lung epithelial cells. Stable expression of 227/236 mutant enhanced migration and invasion as well as cell growth of HSC-2 cells, human oral squamous cancer cell line whose TGF- β signaling is not growth inhibitory. In 227/236 mutant transfectant, E-cadherin expression is reduced whereas snail expression has not been changed significantly. In orthotopic xenograft model to monitor the tumor growth, 227/236 mutant transfectant formed significantly larger tumors as compared to wild type transfectant. But, unexpectedly, there was no difference in the expression pattern of involucrin and E-cadherin in these tumor tissues, suggesting that this mutation did not affect EMT in vivo model system. In the study we present a novel gain-of-function mutation of TGF- β receptor II, which increased TGF- β signaling and thereby induced tumor growth without affecting EMT in HSC-2 oral squamous cancer cells. This work was supported by a grant from the Korea Research Foundation Grant funded by the Korean Government (MOEHRD, Basic research promotion fund KRF-2005-005-J05901). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1494.