Loss of CYLD promotes cell invasion via ALK5 stabilization in oral squamous cell carcinoma
Loss of CYLD promotes cell invasion via ALK5 stabilization in oral squamous cell carcinoma
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DOI：
10.1002/path.5019
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发表时间：
2018-03-01
影响因子：
7.3
通讯作者：
Ando, Yukio
中科院分区：
文献类型：
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作者：
Shinriki, Satoru;Jono, Hirofumi;Ando, Yukio
口腔鳞状细胞癌（Oral squamous cell carcinoma，OSCC）是一种高度侵袭性的恶性肿瘤，其5年生存率在过去的30年里没有明显的变化。虽然圆柱瘤病（CYLD），一种去泛素化酶，被认为是一种有效的肿瘤抑制因子，但其在口腔鳞癌中的生物学和临床意义在很大程度上是未知的。本研究旨在阐明CYLD在OSCC进展中的作用。我们的免疫组化分析显示，CYLD表达显着减少在口腔鳞癌组织中的浸润性领域，而CYLD表达是保守的正常上皮和原位癌。此外，通过siRNA下调CYLD导致OSCC细胞和HaCaT角质形成细胞获得间充质特征并增加迁移和侵袭特性。有趣的是，CYLD敲低通过以细胞自主方式诱导TGF-β受体I（ALK 5）的稳定来促进转化生长因子-β（TGF-β）信号传导。此外，对外源性TGF-β刺激的反应通过CYLD下调而增强。由CYLD敲低诱导的侵袭性表型被ALK 5抑制剂完全阻断。此外，CYLD的低表达与深度浸润和总生存率差的临床特征显著相关，并且还与Smad 3的磷酸化增加相关，Smad 3是浸润性OSCC中TGF-β信号传导激活的指标。这些发现表明CYLD的下调通过ALK 5稳定化促进OSCC细胞的间质转化侵袭。版权所有（C）2017大不列颠和爱尔兰病理学会。由John Wiley & Sons有限公司出版
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 30years. 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-beta (TGF-beta) signalling by inducing stabilization of TGF-beta receptor I (ALK5) in a cell autonomous fashion. In addition, the response to exogenous TGF-beta 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-beta signalling in invasive OSCC. These findings suggest that downregulation of CYLD promotes invasion with mesenchymal transition via ALK5 stabilization in OSCC cells. Copyright (C) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.