Loss of CYLD promotes cell invasion via ALK5 stabilization in oral squamous cell carcinoma. Issue 3 (1st February 2018)

• Record Type: Journal Article
• Authors: Shinriki, Satoru; Jono, Hirofumi; Maeshiro, Manabu; Nakamura, Takuya; Guo, Jianying; Li, Jian‐Dong; Ueda, Mitsuharu; Yoshida, Ryoji; Shinohara, Masanori; Nakayama, Hideki; Matsui, Hirotaka; Ando, Yukio
• Is Part Of: Journal of pathology. Volume 244:Issue 3(2018)
• Page Start: 367
• Page End: 379
• Publication Date: 2018-02-01
• Subjects: CYLD -- transforming growth factor‐β -- ALK5 -- oral squamous cell carcinoma -- mesenchymal transition, invasion; Pathology -- Periodicals; 616.07
• DOI: 10.1002/path.5019
• Languages: English
• ISSNs: 0022-3417

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 tumour 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 the acquisition of mesenchymal features and increased migratory and invasive properties in OSCC cells and HaCaT keratinocytes. It is interesting that CYLD knockdown promoted transforming growth factor‐β (TGF‐β) signalling 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. In addition, lower expression of CYLD was significantly associated with the clinical features of deep invasion and poor overall survival, and also with increased phosphorylation of Smad3, which is an indicator of activation of TGF‐β signalling in invasive OSCC. These findings suggest that downregulation of CYLD promotes invasion with mesenchymal transition via ALK5 stabilization in OSCC cells. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.