Loss of CYLD expression correlates with deep tumor invasion and poor prognosis in patients with invasive oral squamous cell carcinoma

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[Background] Cylindromatosis (CYLD), a tumor suppressor, regulates signaling pathways by acting as a deubiquitinating enzyme. Although recent studies have shown that loss of functional CYLD is potentially-correlated with prognosis of patients with oral squamous cell carcinoma (OSCC), its clinical & biological significances are largely unknown. This study aimed to clarify the roles of CYLD in OSCC progression.

[Results] Immunohistochemical analyses revealed significantly reduced CYLD expression in invasive areas of OSCC tumor tissues. CYLD knockdown by siRNA led to acquisition of mesenchymal features and increased migratory and invasive properties in OSCC cell lines . 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. The invasive phenotypes induced by CYLD knockdown were completely blocked by an ALK5 inhibitor. Moreover, 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 signalling in invasive OSCC.

[Conclusion] Loss of CYLD expression promotes invasion with mesenchymal transition via ALK5 stabilization in OSCC cells.