Abstract 5150: Loss of CYLD promotes cell invasion via ALK5 stabilization in oral squamous cell carcinoma

Abstract

Abstract Oral squamous cell carcinoma (OSCC) has a very poor prognosis because of its highly invasive nature, and the 5-year survival rate has not changed appreciably for the past 30 years. Although cylindromatosis (CYLD), a deubiquitinating enzyme, is thought to be a potent tumor suppressor, its biological and clinical significance in OSCC is largely unknown. This study aimed to clarify the roles of CYLD in OSCC progression. Our immunohistochemical analyses revealed significantly reduced CYLD expression in invasive areas in OSCC tissues, whereas CYLD expression was conserved in normal epithelium and carcinoma in situ. Furthermore, downregulation of CYLD by siRNA led to acquisition of mesenchymal features and increased migratory and invasive properties in OSCC cells and HaCaT keratinocytes. It is interesting that CYLD knockdown promoted TGF-β signaling by inducing stabilization of TGF-β receptor I (ALK5) in a cell autonomous fashion. In addition, the response to exogenous TGF-β stimulation was enhanced by CYLD downregulation. The invasive phenotypes induced by CYLD knockdown were completely blocked by an ALK5 inhibitor. Also, lower CYLD expression was significantly associated with the clinical features of deep invasion, poor overall survival, and increased Smad3 phosphorylation, which is an indicator of activation of TGF-β signaling in invasive OSCC. These findings suggest that downregulation of CYLD promotes invasion with mesenchymal transition via ALK5 stabilization in OSCC cells. Citation Format: Satoru Shinriki, Hirofumi Jono, Manabu Maeshiro, Takuya Nakamura, Jianying Guo, Jian-Dong Li, Ryoji Yoshida, Masanori Shinohara, Hideki Nakayama, Hirotaka Matsui, Yukio Ando. Loss of CYLD promotes cell invasion via ALK5 stabilization in oral squamous cell carcinoma [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 5150.