A Unique Role Of TRPV1 Ion Channels In The Suppression Of Gastric Cancer Development

Abstract

Background: Although the aberrant expression and function of most Ca2+-permeable channels are known to promote gastrointestinal tumors, the association of transient receptor potential vanilloid receptor 1(TRPV1) channels and gastric cancer (GC) has not been explored so far. We sought to determine their role in the development of GC and to elucidate the underlying molecular mechanisms. Methods: The expression of TRPV1 in GC cells and tissues was detected by qPCR, immunohistochemistry, western blot analysis and immunofluorescence. CCK8 and flow cytometry were used to detect the proliferation and cell cycle, while transwell assay was used to detect migration and invasion. The role of TRPV1 in GC development in vivo was tested using tumor xenograft and peritoneal dissemination assays in nude mice. Results: The decreased expression of TRPV1 protein in primary human GC tissues was closely correlated with poor prognosis of GC patients. TRPV1 protein was predominately expressed on the plasma membrane of several GC cell lines. TRPV1 overexpression attenuated proliferation, migration and invasion of GC cells in vitro, but TRPV1 knockdown increased them. Moreover, TRPV1 significantly reduced gastric tumor sizes, numbers and peritoneal dissemination in vivo. Mechanistically, TRPV1 overexpression increased [Ca2+]i, activated CaMKKβ and AMPK phosphorylation, and decreased expression of cyclin D1 and MMP2, but TRPV1 knockdown caused the opposite effects.Conclusions: TRPV1 uniquely suppresses GC through a novel Ca2+/CaMKKβ/AMPK pathway and its downregulation is correlated with poor survival in human GC. TRPV1 upregulation and its downstream signaling may be a promising strategy for GC prevention and therapy.