Abstract
BackgroundAlthough the aberrant expression and function of most Ca2+-permeable channels are known to promote gastrointestinal tumors, the association between transient receptor potential vanilloid receptor 1 (TRPV1) channels and gastric cancer (GC) has not yet been explored. Herein, we sought to determine the role of TRPV1 channels in the development of GC and to elucidate the underlying molecular mechanisms involved therein.MethodsImmunohistochemistry, qPCR, Western blot, immunofluorescence assays were used to detect the mRNA and protein expression of TRPV1 in GC cells and tissues, and the clinical significance of TRPV1 in GC was also studied by clinicopathologic analysis. CCK8, colony formation, flow cytometry assays were used to detect the proliferation and survival of GC cells, while transwell assay was used to detect migration and invasion of GC cells in vitro. Tumor xenograft and peritoneal dissemination assays in nude mice were used to examine the role of TRPV1 in GC development in vivo.ResultsTRPV1 expression was significantly downregulated in human primary GC tissues compared to their adjacent tissues. The decreased expression of TRPV1 proteins in GC tissues was positively correlated with tumor size, histological grade, lymphatic metastasis, clinical stage, and was strongly correlated with poor prognosis of GC patients. Moreover, the expression of TRPV1 was closely correlated with Ki67, VEGFR, and E-cadherin, all of which are the well-known cancer markers for proliferation and metastasis. TRPV1 proteins were predominately expressed on the plasma membrane in several GC cell lines. TRPV1 overexpression blocked cell cycle at G1 phase to inhibit GC cell proliferation and attenuated migration and invasion of GC cells in vitro, but TRPV1 knockdown increased these parameters. TRPV1 significantly reduced gastric tumor size, number and peritoneal dissemination in vivo. Mechanistically, TRPV1 overexpression in GC cells increased [Ca2+]i, activated CaMKKβ and AMPK phosphorylation, and decreased expression of cyclin D1 and MMP2, while TRPV1 knockdown induced the opposite effects.ConclusionsTRPV1 uniquely suppresses GC development through a novel Ca2+/CaMKKβ/AMPK pathway and its downregulation is correlated with poor survival of human GC patients. Thus, TRPV1 upregulation and its downstream signaling may represent a promising target for GC prevention and therapy.
Highlights
The aberrant expression and function of most Ca2+-permeable channels are known to promote gastrointestinal tumors, the association between transient receptor potential vanilloid receptor 1 (TRPV1) channels and gastric cancer (GC) has not yet been explored
In the present study, we revealed that: (a) the expression of TRPV1 channel at the levels of mRNA and proteins was significantly decreased in human primary GC tissues; (b) the downregulation of TRPV1 expression was closely correlated with poor GC progression; (c) TRPV1 inhibited proliferation, migration and invasion of GC cells in vitro, and reduced gastric tumor size, number and peritoneal dissemination in vivo; and (d) mechanistically, TRPV1 suppresses GC progression through Ca2+/ Calcium/ calmodulin-dependent protein kinase kinase β (CaMKKβ)/Adenosine mono phosphate activated protein kinase (AMPK) signaling pathway to reduce cyclin D1 and matrix metalloproteinase-2 (MMP2) expression
We have verified that TRPV1 expression is downregulated in human primary GC tissues compared to their adjacent tissues, which is consistent with the prediction from the Oncomine tumor database
Summary
The aberrant expression and function of most Ca2+-permeable channels are known to promote gastrointestinal tumors, the association between transient receptor potential vanilloid receptor 1 (TRPV1) channels and gastric cancer (GC) has not yet been explored. The occurrence and progression of cancer are complex, numerous findings indicate that aberrant intracellular Ca2+ ([Ca2+]i) signaling is involved in the development of several types of gastrointestinal (GI) cancers, including GC and colon cancer [4]. Since plasma membrane Ca2+-permeable channels play important roles in the regulation of [Ca2+]i, their aberrant expression and function are positively associated with the occurrence and development of GI tumors [5, 6]. The Ca2+-permeable TRPV channels deserve further intensive investigation since they could be novel potential drug targets for GI tumor therapy [9]
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
More From: Journal of Experimental & Clinical Cancer Research
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.