VPAC1 couples with TRPV4 channel to promote calcium-dependent gastric cancer progression via a novel autocrine mechanism
VPAC1 couples with TRPV4 channel to promote calcium-dependent gastric cancer progression via a novel autocrine mechanism
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VPAC1与TRPV4通道结合通过一种新的自分泌机制促进钙依赖性胃癌进展
DOI：
10.1038/s41388-019-0709-6
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发表时间：
2019-05-16
期刊：
影响因子：
8
通讯作者：
Dong, Hui
中科院分区：
文献类型：
--
作者：
Tang, Bo;Wu, Jilin;Dong, Hui
虽然VPAC1及其配体血管活性肠肽(VIP)在胃肠道生理学中具有重要作用，但其在胃肠道肿瘤发生发展中的作用尚未见报道。在此，我们发现VIP/VPAC1在胃癌组织中的表达高于癌旁正常组织。VIP/VPAC1在胃癌组织中的高表达与肿瘤的侵袭程度、分期、有无淋巴结转移、远处转移及预后不良呈正相关。此外，VIP和VPAC1的高表达、肿瘤分期和远处转移是影响预后的独立因素。VIP激活VPAC1可显著诱导TRPV4介导的钙内流，最终以钙信号依赖的方式促进胃癌的进展。抑制VPAC1及其信号通路可阻断进行性反应。VPAC1/TRPV4/Ca~(2+)信号转而促进胃癌细胞VIP的表达和分泌，形成正反馈调节机制。综上所述，我们的研究表明VPAC1在胃癌中显著过表达，VPAC1/TRPV4/钙信号转导轴在胃癌进展过程中可能起到正反馈调节作用。VIP/VPAC1可能成为胃癌的潜在预后标志物和治疗靶点。
Although VPAC1 and its ligand vasoactive intestinal peptide (VIP) are important in gastrointestinal physiology, their involvements in progression of gastrointestinal tumor have not been explored. Here, we found that higher expression of VIP/VPAC1 was observed in gastric cancer compared to the adjacent normal tissues. The increased expression of VIP/VPAC1 in gastric cancer correlated positively with invasion, tumor stage, lymph node, distant metastases, and poor survival. Moreover, high expression of VIP and VPAC1, advanced tumor stage and distant metastasis were independent prognostic factors. VPAC1 activation by VIP markedly induced TRPV4-mediated Ca2+entry, and eventually promoted gastric cancer progression in a Ca2+signaling-dependent manner. Inhibition of VPAC1 and its signaling pathway could block the progressive responses. VPAC1/TRPV4/Ca2+signaling in turn enhanced the expression and secretion of VIP in gastric cancer cells, enforcing a positive feedback regulation mechanism. Taken together, our study demonstrate that VPAC1 is significantly overexpressed in gastric cancer and VPAC1/TRPV4/Ca2+signaling axis could enforce a positive feedback regulation in gastric cancer progression. VIP/VPAC1 may serve as potential prognostic markers and therapeutic targets for gastric cancer.