Regulation of the Hippo/YAP axis by CXCR7 in the tumorigenesis of gastric cancer

作者：Tianshi Wang, Dehai Wang, Yanan Sun, Ting Zhuang, Xin Li, Huijie Yang, Yifeng Zang, Ziping Liu, Penghe Yang, Chenmiao Zhang, Jiayao Cui, Mingxi Fu, Shuqing Zhang, Peng Su, Zhongbo Li, Jian Zhu, Yinlu Ding · 发表于：Journal of Experimental & Clinical Cancer Research · 年份：2023 · DOI：10.1186/s13046-023-02870-3 · 被引用次数：27 · 研究领域：Hippo pathway signaling and YAP/TAZ、Cancer-related molecular mechanisms research、Proteoglycans and glycosaminoglycans research

Abstract Background The Hippo pathway is crucial in organ size control and tumorigenesis. Dysregulation of the Hippo/YAP axis is commonly observed in gastric cancer, while effective therapeutic targets for the Hippo/YAP axis are lacking. Identification of reliable drug targets and the underlying mechanisms that could inhibit the activity of the Hippo/YAP axis and gastric cancer progression is urgently needed. Methods We used several gastric cancer cell lines and xenograft models and performed immunoblotting, qPCR, and in vivo studies to investigate the function of CXCR7 in gastric cancer progression. Results In our current study, we demonstrate that the membrane receptor CXCR7 (C-X-C chemokine receptor 7) is an important modulator of the Hippo/YAP axis. The activation of CXCR7 could stimulate gastric cancer cell progression through the Hippo/YAP axis in vitro and in vivo, while pharmaceutical inhibition of CXCR7 via ACT-1004–1239 could block tumorigenesis in gastric cancer. Molecular studies revealed that the activation of CXCR7 could dephosphorylate YAP and facilitate YAP nuclear accumulation and transcriptional activation in gastric cancer. CXCR7 functions via G-protein Gα q/11 and Rho GTPase to activate YAP activity. Interestingly, ChIP assays showed that YAP could bind to the promoter region of CXCR7 and facilitate its gene transcription, which indicates that CXCR7 is both the upstream signalling and downstream target of the Hippo/YAP axis in gastric cancer. Conclusion In...