Department of Urology, Tangdu Hospital, Air Force Medical University, Xi'an, Shaanxi, China.
Department of Gastroenterology, The Second Affiliated Hospital of Shandong First Medical University, Taian, Shandong, China.
Carcinogenesis. 2022 May 19;43(4):301-310. doi: 10.1093/carcin/bgac014.
Renal cell carcinoma (RCC) is characterized by substantial vasculatures and increased fluid movement in tumor microenvironment, and the fluid shear stress modulates malignance, extravasation and metastatic seeding of tumor cells. However, the precise mechanism remains largely unclear. In this study, we found that low shear stress induced the Yes-associated protein (YAP1) activation and nuclear localization in RCC cells, as well as the downregulation of phosphorylated YAP1 at Ser127. Moreover, inhibition of ROCK or RhoA partially abolished YAP1 accumulation in the nucleus, and targeting YAP1 activation by small molecular inhibitor or genetic manipulation decreased the low shear stress-induced epithelial-mesenchymal transition (EMT) of RCC cells, and led to a decreased expression of N-cadherin as accompanied by downregulation of SNAIL1 and TWIST, accompanied by high shear stress-induced cell apoptosis. Salvianolic acid B, an aqueous component of danshen (Salvia miltiorrhiza), inhibited YAP1 and Hippo signaling activation, and abrogated low shear stress-induced EMT as a consequence. Taken together, our study suggests YAP1 is a fluid mechanosensor that transforms mechanical stimuli to cell signals, thereby facilitates anoikis resistance and tumor metastasis.
肾细胞癌（RCC）的特征是肿瘤微环境中存在大量血管和增加的流体运动，流体剪切应力调节肿瘤细胞的恶性程度、渗出和转移播种。然而，确切的机制在很大程度上仍不清楚。在这项研究中，我们发现低剪切应力诱导 RCC 细胞中 Yes 相关蛋白（YAP1）的激活和核定位，以及磷酸化 YAP1 在 Ser127 位点的下调。此外，抑制 ROCK 或 RhoA 部分消除了 YAP1 在核内的积累，而通过小分子抑制剂或遗传操作靶向 YAP1 激活可降低低剪切应力诱导的 RCC 细胞上皮-间充质转化（EMT），并导致 N-钙黏蛋白表达降低，同时伴随着 SNAIL1 和 TWIST 的下调，伴随高剪切应力诱导的细胞凋亡。丹酚酸 B，丹参（Salvia miltiorrhiza）的水性成分，抑制了 YAP1 和 Hippo 信号通路的激活，并由此消除了低剪切应力诱导的 EMT。总之，我们的研究表明 YAP1 是一种流体机械感受器，可将机械刺激转化为细胞信号，从而促进失巢凋亡抵抗和肿瘤转移。
