VPAC1 couples with TRPV4 channel to promote calcium-dependent gastric cancer progression via a novel autocrine mechanism

Bo Tang; Jilin Wu; Michael X Zhu; Xuemei Sun; Jingjing Liu; Rui Xie; Tobias Xiao Dong; Yufeng Xiao; John M Carethers; Shiming Yang; Hui Dong

doi:10.1038/s41388-019-0709-6

VPAC1 couples with TRPV4 channel to promote calcium-dependent gastric cancer progression via a novel autocrine mechanism

Oncogene. 2019 May;38(20):3946-3961. doi: 10.1038/s41388-019-0709-6. Epub 2019 Jan 28.

Authors

Bo Tang^{1

2}, Jilin Wu^{3

4}, Michael X Zhu^{3

5}, Xuemei Sun¹, Jingjing Liu¹, Rui Xie^{1

6}, Tobias Xiao Dong², Yufeng Xiao¹, John M Carethers⁷, Shiming Yang⁸, Hui Dong^{9

10}

Affiliations

¹ Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
² Department of Medicine, School of Medicine, University of California, San Diego, CA, USA.
³ Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
⁴ University of Chinese Academy of Sciences, Beijing, China.
⁵ Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.
⁶ Department of Gastroenterology, Affiliated Hospital to Zunyi Medical College, Zunyi, China.
⁷ Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
⁸ Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China. shimingyang@yahoo.com.
⁹ Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China. h2dong@ucsd.edu.
¹⁰ Department of Medicine, School of Medicine, University of California, San Diego, CA, USA. h2dong@ucsd.edu.

PMID: 30692637
DOI: 10.1038/s41388-019-0709-6

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Calcium / metabolism*
Cell Line, Tumor
Cell Movement
Humans
Kaplan-Meier Estimate
Lung Neoplasms / secondary
Male
Mice, Inbred BALB C
Receptors, Vasoactive Intestinal Polypeptide, Type I / genetics
Receptors, Vasoactive Intestinal Polypeptide, Type I / metabolism*
Stomach Neoplasms / metabolism
Stomach Neoplasms / mortality*
Stomach Neoplasms / pathology*
TRPV Cation Channels / genetics
TRPV Cation Channels / metabolism*
Vasoactive Intestinal Peptide / metabolism
Xenograft Model Antitumor Assays

Substances

Receptors, Vasoactive Intestinal Polypeptide, Type I
TRPV Cation Channels
TRPV4 protein, human
Vasoactive Intestinal Peptide
Calcium