Abstract
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.
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Acknowledgements
This work was supported by the National Key Research and Development Program of China (No. 2016YFC1302200 to HD), National Natural Science Foundation of China (No. 81602577 to BT), and Basic Science and Frontier Technology Research Project of Chongqing (No. cstc2017jcyjAX0149 to BT).
Author contributions
HD and SY conceived of the study; BT and MXZ designed the experiments; BT, JW, XS, JL, RX, TD, and YX performed the experiments; BT and JW performed analysis and interpretation of data; HD and BT wrote the manuscript; MXZ, JMC, and SY critically reviewed the manuscript.
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Tang, B., Wu, J., Zhu, M.X. et al. VPAC1 couples with TRPV4 channel to promote calcium-dependent gastric cancer progression via a novel autocrine mechanism. Oncogene 38, 3946–3961 (2019). https://doi.org/10.1038/s41388-019-0709-6
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DOI: https://doi.org/10.1038/s41388-019-0709-6
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