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| Abstract |
Most cancer cells are exposed to extracellular environments, such as an increase in extracellular matrix (ECM) stiffness with genetic transformation of cancer cells and soluble signals consisting of g...rowth factors and cytokines. It is therefore conceivable that changes in the tumorous extracellular environments would affect tumor cell behavior. The Hippo pathway reportedly responds to the extracellular environment and regulates the nuclear localization of the transcription co-activator, yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ). Inactivation of the Hippo pathway with nuclear translocation of YAP/TAZ leads to stimulate cell proliferation. Its pathway also regulates gene expression, but the precise molecule meditating the cell-proliferating effect of YAP signaling on oral squamous cell carcinoma (OSCC) is unclear. First, we examined the effects of YAP signaling on OSCC tumorigenesis. Loss-of-function experiments using siRNA or an inhibitor, and immunohistochemical analyses of tissue specimens obtained from OSCC patients demonstrated that YAP signaling was involved in OSCC cell proliferation. Second, we identified Piezo-type mechanosensitive ion channel component 1 (PIEZO1), a Ca2+ channel, as a transcriptional target of YAP signaling and showed that an elevated PIEZO1 expression was required for PIEZO1 agonist-dependent Ca2+ entry and cell proliferation in OSCC cells. Furthermore, experiments using three-dimensional culture and suspension culture revealed that PIEZO1, the expression of which is regulated by YAP signaling, was involved in OSCC cellular growth. Finally, YAP overexpression in the nucleus and/or cytoplasm was immunohistochemically detected in tumor lesions with high frequent expression of both PIEZO1 and Ki-67 but not in non-tumor regions of OSCC specimens. These results suggest that the YAP/PIEZO1 axis promotes OSCC cell growth.show more
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