Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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

Oncogene volume 38, pages 3946–3961 (2019)Cite this article

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. Cancer J Clin. 2016;66:7–30.

    Article  Google Scholar 

  2. Tan P, Yeoh KG. Genetics and molecular pathogenesis of gastric adenocarcinoma. Gastroenterology. 2015;149:1153–62.

    Article  CAS  Google Scholar 

  3. Badgwell B, Blum M, Estrella J, Ajani J. Personalised therapy for localised gastric and gastro-oesophageal adenocarcinoma. Lancet Oncol. 2016;17:1628–9.

    Article  Google Scholar 

  4. Vacas E, Bajo AM, Schally AV, Sánchez-Chapado M, Prieto JC, Carmena MJ. Vasoactive intestinal peptide induces oxidative stress and suppresses metastatic potential in human clear cell renal cell carcinoma. Mol Cell Endocrinol. 2013;365:212–22.

    Article  CAS  Google Scholar 

  5. Vacas E, Arenas MI, Muñoz-Moreno L, Bajo AM, Sánchez-Chapado M, Prieto JC, et al. Antitumoral effects of vasoactive intestinal peptide in human renal cell carcinoma xenografts in athymic nude mice. Cancer Lett. 2013;336:196–203.

    Article  CAS  Google Scholar 

  6. Seoane IV, Ortiz AM, Piris L, Lamana A, Juarranz Y, García-Vicuña R, et al. Clinical relevance of VPAC1 receptor expression in early arthritis: association with IL-6 and disease activity. PLoS One. 2016;11:e0149141.

    Article  Google Scholar 

  7. White CM, Ji S, Cai H, Maudsley S, Martin B. Therapeutic potential of vasoactive intestinal peptide and its receptors in neurological disorders. CNS Neurol Disord Drug Targets. 2010;9:661–6.

    Article  CAS  Google Scholar 

  8. Valdehita A, Bajo AM, Schally AV, Varga JL, Carmena MJ, Prieto JC. Vasoactive intestinal peptide (VIP) induces transactivation of EGFR and HER2 in human breast cancer cells. Mol Cell Endocrinol. 2009;302:41–8.

    Article  CAS  Google Scholar 

  9. Valdehita A, Carmena MJ, Collado B, Prieto JC, Bajo AM. Vasoactive intestinal peptide (VIP) increases vascular endothelial growth factor (VEGF) expression and secretion in human breast cancer cells. Regul Pept. 2007;144:101–8.

    Article  CAS  Google Scholar 

  10. Reubi JC, Läderach U, Waser B, Gebbers JO, Robberecht P, Laissue JA. Vasoactive intestinal peptide/pituitary adenylate cyclase-activating peptide receptor subtypes in human tumors and their tissues of origin. Cancer Res. 2000;60:3105–12.

    CAS  PubMed  Google Scholar 

  11. Fernández-Martínez AB, Carmena MJ, Arenas MI, Bajo AM, Prieto JC, Sánchez-Chapado M. Overexpression of vasoactive intestinal peptide receptors and cyclooxygenase-2 in human prostate cancer. Anal Potential Progn Relev Histol Histopathol. 2012;27:1093–101.

    Google Scholar 

  12. Liu S, Zeng Y, Li Y, Guo W, Liu J, Ouyang N. VPAC1 overexpression is associated with poor differentiation in colon cancer. Tumour Biol. 2014;35:6397–404.

    Article  CAS  Google Scholar 

  13. Dickson L, Finlayson K. VPAC and PAC receptors: from ligands to function. Pharmacol Ther. 2009;121:294–316.

    Article  CAS  Google Scholar 

  14. Zhang S, Liu Y, Guo S, Zhang J, Chu X, Jiang C, et al. Vasoactive intestinal polypeptide relaxes isolated rat pulmonary artery rings through two distinct mechanisms. J Physiol Sci. 2010;60:389–97.

    Article  CAS  Google Scholar 

  15. Herrera JL, Gonzalez-Rey E, Fernandez-Montesinos R, Quintana FJ, Najmanovich R, Pozo D. Toll-like receptor stimulation differentially regulates vasoactive intestinal peptide type 2 receptor in macrophages. J Cell Mol Med. 2009;13:3209–17.

    Article  Google Scholar 

  16. Berridge MJ, Bootman MD, Roderick HL. Calcium signalling: dynamics, homeostasis and remodelling. Nat Rev Mol Cell Biol. 2003;4:517–29.

    Article  CAS  Google Scholar 

  17. Monteith GR, Davis FM, Roberts-Thomson SJ. Calcium channels and pumps in cancer: changes and consequences. J Biol Chem. 2012;287:31666–73.

    Article  CAS  Google Scholar 

  18. Fiorio Pla A, Ong HL, Cheng KT, Brossa A, Bussolati B, Lockwich T, et al. TRPV4 mediates tumor-derived endothelial cell migration via arachidonic acid-activated actin remodeling. Oncogene. 2012;31:200–12.

    Article  CAS  Google Scholar 

  19. Wei C, Wang X, Chen M, Ouyang K, Song LS, Cheng H. Calcium flickers steer cell migration. Nature. 2009;457:901–5.

    Article  CAS  Google Scholar 

  20. Evans AM, Fameli N, Ogunbayo OA, Duan J, Navarro-Dorado J. From contraction to gene expression: nanojunctions of the sarco/endoplasmic reticulum deliver site- and function-specific calcium signals. Sci China Life Sci. 2016;59:749–63.

    Article  CAS  Google Scholar 

  21. Hofer AM, Brown EM. Extracellular calcium sensing and signalling. Nat Rev Mol Cell Biol. 2003;4:530–8.

    Article  CAS  Google Scholar 

  22. Déliot N, Constantin B. Plasma membrane calcium channels in cancer: alterations and consequences for cell proliferation and migration. Biochim Biophys Acta. 2015;1848:2512–22.

    Article  Google Scholar 

  23. Holzer P. TRP channels in the digestive system. Curr Pharm Biotechnol. 2011;12:24–34.

    Article  CAS  Google Scholar 

  24. D’Aldebert E, Cenac N, Rousset P, Martin L, Rolland C, Chapman K, et al. Transient receptor potential vanilloid 4 activated inflammatory signals by intestinal epithelial cells and colitis in mice. Gastroenterology. 2011;140:275–85.

    Article  Google Scholar 

  25. Xie R, Xu J, Xiao Y, Wu J, Wan H, Tang B, et al. Calcium promotes human gastric cancer via a novel coupling of calcium-sensing receptor and TRPV4 channel. Cancer Res. 2017;77:6499–512.

    Article  CAS  Google Scholar 

  26. Chen YF, Hsu KF, Shen MR. The store-operated Ca(2+) entry-mediated signaling is important for cancer spread. Biochim Biophys Acta. 2016;1863:1427–35.

    Article  CAS  Google Scholar 

  27. Chen YF, Chen YT, Chiu WT, Shen MR. Remodeling of calcium signaling in tumor progression. J Biomed Sci. 2013;20:23.

    Article  CAS  Google Scholar 

  28. Zhu MX, Tuo B, Yang JJ. The hills and valleys of calcium signaling. Sci China Life Sci. 2016;59:743–8.

    Article  Google Scholar 

  29. Leuner K, Heiser JH, Derksen S, Mladenov MI, Fehske CJ, Schubert R, et al. Simple 2,4-diacylphloroglucinols as classic transient receptor potential-6 activators—identification of a novel pharmacophore. Mol Pharmacol. 2010;77:368–77.

    Article  CAS  Google Scholar 

  30. Storch U, Forst AL, Pardatscher F, Erdogmus S, Philipp M, Gregoritza M, et al. Dynamic NHERF interaction with TRPC4/5 proteins is required for channel gating by diacylglycerol. Proc Natl Acad Sci USA. 2017;114:E37–E46.

    Article  CAS  Google Scholar 

  31. Xiao G, Wang X, Wang J, Zu L, Cheng G, Hao M, et al. CXCL16/CXCR6 chemokine signaling mediates breast cancer progression by pERK1/2-dependent mechanisms. Oncotarget. 2015;6:14165–78.

    PubMed  PubMed Central  Google Scholar 

  32. Song W, Ma Y, Wang J, Brantley-Sieders D, Chen J. JNK signaling mediates EPHA2-dependent tumor cell proliferation, motility, and cancer stem cell-like properties in non-small cell lung cancer. Cancer Res. 2014;74:2444–54.

    Article  CAS  Google Scholar 

  33. Ma Y, Yang Y, Wang F, Moyer MP, Wei Q, Zhang P, et al. Long non-coding RNA CCAL regulates colorectal cancer progression by activating Wnt/β-catenin signalling pathway via suppression of activator protein 2α. Gut. 2016;65:1494–504.

    Article  CAS  Google Scholar 

  34. Hejna M, Hamilton G, Brodowicz T, Haberl I, Fiebiger WC, Scheithauer W, et al. Serum levels of vasoactive intestinal peptide (VIP) in patients with adenocarcinomas of the gastrointestinal tract. Anticancer Res. 2001;21:1183–7.

    CAS  PubMed  Google Scholar 

  35. Yin Y, Gao D, Wang Y, Wang ZH, Wang X, Ye J, et al. Tau accumulation induces synaptic impairment and memory deficit by calcineurin-mediated inactivation of nuclear CaMKIV/CREB signaling. Proc Natl Acad Sci USA. 2016;113:E3773–3781.

    Article  CAS  Google Scholar 

  36. Hogan PG. Calcium-NFAT transcriptional signalling in T cell activation and T cell exhaustion. Cell Calcium. 2017;63:66–9.

    Article  CAS  Google Scholar 

  37. Chen F, Zhuang X, Lin L, Yu P, Wang Y, Shi Y, et al. New horizons in tumor microenvironment biology: challenges and opportunities. BMC Med. 2015;13:45.

    Article  Google Scholar 

  38. Galione A, Churchill GC. Interactions between calcium release pathways: multiple messengers and multiple stores. Cell Calcium. 2002;32:343–54.

    Article  CAS  Google Scholar 

  39. Li D, Jiao J, Shatos MA, Hodges RR, Dartt DA. Effect of VIP on intracellular [Ca2+], extracellular regulated kinase 1/2, and secretion in cultured rat conjunctival goblet cells. Invest Ophthalmol Vis Sci. 2013;54:2872–84.

    Article  CAS  Google Scholar 

  40. Hagen BM, Bayguinov O, Sanders KM. VIP and PACAP regulate localized Ca2+ transients via cAMP-dependent mechanism. Am J Physiol Cell Physiol. 2006;291:C375–85.

    Article  CAS  Google Scholar 

  41. Woo DH, Jung SJ, Zhu MH, Park CK, Kim YH, Oh SB, et al. Direct activation of transient receptor potential vanilloid 1(TRPV1) by diacylglycerol (DAG). Mol Pain. 2008;4:42.

    Article  Google Scholar 

  42. Kodama D, Togari A. Store-operated calcium entry induced by activation of Gq-coupled alpha1B adrenergic receptor in human osteoblast. Biochem Biophys Res Commun. 2013;437:239–44.

    Article  CAS  Google Scholar 

  43. Andrikopoulos P, Kieswich J, Harwood SM, Baba A, Matsuda T, Barbeau O, et al. Endothelial angiogenesis and barrier function in response to thrombin require Ca2+ Influx through the Na+/Ca2+ exchanger. J Biol Chem. 2015;290:18412–28.

    Article  CAS  Google Scholar 

  44. Favia A, Desideri M, Gambara G, D’Alessio A, Ruas M, Esposito B, et al. VEGF-induced neoangiogenesis is mediated by NAADP and two-pore channel-2-dependent Ca2+ signaling. Proc Natl Acad Sci USA. 2014;111:E4706–4715.

    Article  CAS  Google Scholar 

  45. Thrasivoulou C, Millar M, Ahmed A. Activation of intracellular calcium by multiple Wnt ligands and translocation of β-catenin into the nucleus: a convergent model of Wnt/Ca2+ and Wnt/β-catenin pathways. J Biol Chem. 2013;288:35651–9.

    Article  CAS  Google Scholar 

  46. Tabuchi A, Sakaya H, Kisukeda T, Fushiki H, Tsuda M. Involvement of an upstream stimulatory factor as well as cAMP-responsive element-binding protein in the activation of brain-derived neurotrophic factor gene promoter I. J Biol Chem. 2002;277:35920–31.

    Article  CAS  Google Scholar 

  47. Hahm SH, Eiden LE. Cis-regulatory elements controlling basal and inducible VIP gene transcription. Ann N Y Acad Sci. 1998;865:10–26.

    Article  CAS  Google Scholar 

  48. Schwarz EC, Qu B, Hoth M. Calcium, cancer and killing: the role of calcium in killing cancer cells by cytotoxic T lymphocytes and natural killer cells. Biochim Biophys Acta. 2013;1833:1603–11.

    Article  CAS  Google Scholar 

  49. Tompkins JD, Girard BM, Vizzard MA, Parsons RL. VIP and PACAP effects on mouse major pelvic ganglia neurons. J Mol Neurosci. 2010;42:390–6.

    Article  CAS  Google Scholar 

  50. Liu F, Cao QH, Lu DJ, Luo B, Lu XF, Luo RC, et al. TMEM16A overexpression contributes to tumor invasion and poor prognosis of human gastric cancer through TGF-β signaling. Oncotarget. 2015;6:11585–99.

    PubMed  PubMed Central  Google Scholar 

  51. Zhou Z, Ji Z, Wang Y, Li J, Cao H, Zhu HH, et al. TRIM59 is upregulated in gastric tumors, promoting ubiquitination and degradation of p53. Gastroenterology. 2014;147:1043–54.

    Article  CAS  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  1. Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China

    Bo Tang, Xuemei Sun, Jingjing Liu, Rui Xie, Yufeng Xiao, Shiming Yang & Hui Dong

  2. Department of Medicine, School of Medicine, University of California, San Diego, CA, USA

    Bo Tang, Tobias Xiao Dong & Hui Dong

  3. Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China

    Jilin Wu & Michael X. Zhu

  4. University of Chinese Academy of Sciences, Beijing, China

    Jilin Wu

  5. Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA

    Michael X. Zhu

  6. Department of Gastroenterology, Affiliated Hospital to Zunyi Medical College, Zunyi, China

    Rui Xie

  7. Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA

    John M. Carethers

Authors
  1. Bo Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jilin Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michael X. Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xuemei Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jingjing Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rui Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tobias Xiao Dong
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yufeng Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. John M. Carethers
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Shiming Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Hui Dong
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Shiming Yang or Hui Dong.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-019-0709-6

This article is cited by

Search

Advanced search

Quick links