Calcium promotes human gastric cancer via a novel coupling of calcium-sensing receptor and TRPV4 channel

Although dietary calcium intake has long been recommended for disease prevention, the influence of calcium in development of cancer in the upper gastrointestinal tract has not been explored. Here we assess the roles of calcium and calcium-sensing receptor (CaSR) in gastric cancer (GC) development. CaSR expression was enhanced in GC specimens, which positively correlated with serum calcium concentrations, tumor progression, poor survival, and male gender in GC patients. CaSR and transient receptor potential cation channel subfamily V member 4 (TRPV4) were co-localized in GC cells, and CaSR activation evoked TRPV4-mediated Ca2+ entry. Both CaSR and TRPV4 were involved in Ca2+-induced proliferation, migration, and invasion of GC cells through a Ca2+/AKT/β-catenin relay which occurred only in GC cells or normal cells overexpressing CaSR. Tumor growth and metastasis of GC depended on CaSR in nude mice. Overall, our findings indicate that calcium may enhance expression and function of CaSR to potentially promote GC, and that targeting the novel CaSR/TRPV4/ Ca2+ pathway might serve as preventive or therapeutic strategies for GC.

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