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

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...

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Published in:The Journal of pathology 2018-03, Vol.244 (3), p.367-379
Main 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
Format: Article
Language:English
Subjects:
ALK5
CYLD
Epithelium
Invasiveness
Keratinocytes
Medical prognosis
mesenchymal transition, invasion
Mesenchyme
Oral cancer
Oral squamous cell carcinoma
Phosphorylation
siRNA
Smad3 protein
Squamous cell carcinoma
Stabilization
Tissues
Transforming growth factor-b
transforming growth factor‐β
Tumors
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Summary: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.
ISSN:0022-3417
1096-9896
DOI:10.1002/path.5019