The 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 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. Methods Immunohistochemistry, 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. Results TRPV1 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. Conclusions TRPV1 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.

Mecanismos envolvidos no efeito anticarcinogênico da desnervação mientérica do cólon

“…This finding is coherent with reports in the literature data showing the anti-tumor properties of TRPV1 (38,39) . A positive correlation between TRPV1 expression and histopathologic differentiation of human hepatocellular carcinoma (HCC) has been observed, as well as a better clinical prognosis in patients with HCC associated with high TRPV1 expression levels (40) .…”

FHOD1 is upregulated in gastric cancer and promotes the proliferation and invasion of gastric cancer cells

“…The development of GC is considered as a multifactorial process involving cell proliferation, tumor growth, ECM degradation, cell adhesion and motility, and angiogenesis (21)(22)(23)(24)(25). The regulation of these cellular processes involves oncogenes and tumor suppressor genes, and their corresponding encoded products and pathways.…”

The Effects of Capsaicin on Gastrointestinal Cancers

“…BCL-2 is an antiapoptotic protein, responsible for the regulation of the transmembrane calcium fluxes. Dysfunction of calcium-permeable channels was revealed as a possible inducer for cancer development, including gastrointestinal tumors [ 70 ]. Ca 2+ is a main factor in the process of apoptosis and BCL-2 is blocking the programmed cell death induced by Ca 2+ -ionophores in various cell lines such as thymocytes, T-cell leukemia lines, and PC12 cells [ 71 ].…”