Abstract 4314: Loss of CYLD promotes cell migration through stabilized ALK5 in human oral squamous cell carcinoma cells.

Abstract

Abstract Five-year survival of patients with oral squamous cell carcinoma (OSCC) has not changed apparently for the past 30 years. Although cylindromatosis (CYLD) is thought as a potent tumor suppressor, its biological significances in malignancies are largely unknown. The aim of this study was to clarify the role of CYLD in OSCC progression. We investigated expression of CYLD in OSCC including intraepithelial neoplasia (IEN; n = 48) and invasive carcinomas (n = 133) tissues and normal oral mucosal tissues (n = 35) by immunohistochemistry. In addition, effects of CYLD knockdown by siRNA or its overexpression on OSCC progression using OSCC cell lines. Our immunohistochemical analyses revealed that CYLD expression was significantly reduced at invasive lesions in OSCC tissues whereas it was conserved in normal epithelium and IEN. In addition, lower CYLD expression was associated with poor overall survival in invasive OSCC. Accordingly, CYLD knockdown led to acquisition of mesenchymal state and increased migratory activity in OSCC cells. Interestingly, loss of CYLD enhanced TGFβR1 (ALK5) protein expression by promoting ALK5 stability while overexpression of wild-type CYLD downregulated ALK5. Furthermore, EMT-like changes induced by CYLD knockdown were completely blocked by a TGFβR1 kinase inhibitor in OSCC cells. These findings suggest that downregulation of CYLD promotes invasion through EMT-like changes via ALK5 stabilization in OSCC cells. Further studies for these mechanisms probably provide new insights into the TGFβ signal transduction in cancer and development of a novel therapy in OSCC. Citation Format: Satoru Shinriki, Hirofumi Jono, Jian-Dong Li, Takuya Nakamura, Mitsuhiro Hayashi, Jianying Guo, Masanori Shinohara, Yukio Ando. Loss of CYLD promotes cell migration through stabilized ALK5 in human oral squamous cell carcinoma cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4314. doi:10.1158/1538-7445.AM2013-4314