Laboratory of Oral Pathology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan.
Department of Molecular Biology and Biochemistry, Graduate School of Medicine, Osaka University, Suita, Japan.
J Pathol. 2021 Jan;253(1):80-93. doi: 10.1002/path.5553. Epub 2020 Nov 5.
Most cancer cells are exposed to altered extracellular environments, such as an increase in extracellular matrix (ECM) stiffness and soluble signals consisting of growth factors and cytokines. It is therefore conceivable that changes in tumor extracellular environments 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 stimulates cell proliferation. Its pathway also regulates gene expression, but the precise molecule(s) 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 Ca channel, as a transcriptional target of YAP signaling and showed that elevated PIEZO1 was required for PIEZO1 agonist-dependent Ca entry and cell proliferation in OSCC cells. Experiments using three-dimensional and suspension culture revealed that PIEZO1 was involved in OSCC cellular growth. Finally, YAP overexpression in the nucleus and/or cytoplasm was immunohistochemically detected in tumor lesions with 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. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
大多数癌细胞都暴露于改变的细胞外环境中，例如细胞外基质（ECM）硬度的增加和由生长因子和细胞因子组成的可溶性信号。因此，可以想象肿瘤细胞外环境的变化会影响肿瘤细胞的行为。据报道，Hippo 通路响应细胞外环境，并调节转录共激活因子 yes 相关蛋白（YAP）/含 PDZ 结合基序的转录共激活因子（TAZ）的核定位。YAP/TAZ 的 Hippo 通路失活和核转位刺激细胞增殖。其通路还调节基因表达，但介导 YAP 信号对口腔鳞状细胞癌（OSCC）的细胞增殖作用的确切分子尚不清楚。首先，我们研究了 YAP 信号对 OSCC 肿瘤发生的影响。使用 siRNA 或抑制剂的功能丧失实验，以及从 OSCC 患者获得的组织标本的免疫组织化学分析表明，YAP 信号参与了 OSCC 细胞增殖。其次，我们确定了 Piezo 型机械敏感离子通道成分 1（PIEZO1），一种 Ca 通道，作为 YAP 信号的转录靶标，并表明升高的 PIEZO1 是 PIEZO1 激动剂依赖性 Ca 内流和 OSCC 细胞增殖所必需的。使用三维和悬浮培养的实验表明，PIEZO1 参与了 OSCC 细胞的生长。最后，在肿瘤病变中免疫组织化学检测到核内和/或细胞质中的 YAP 过度表达，这些肿瘤病变中 PIEZO1 和 Ki-67 的表达频繁，但在 OSCC 标本的非肿瘤区域未检测到。这些结果表明，YAP/PIEZO1 轴促进 OSCC 细胞生长。©2020 英国和爱尔兰病理学会。由 John Wiley & Sons，Ltd 出版。
