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.
Subject(s)
Calcium/metabolism , Receptors, Vasoactive Intestinal Polypeptide, Type I/metabolism , Stomach Neoplasms/mortality , Stomach Neoplasms/pathology , TRPV Cation Channels/metabolism , Animals , Cell Line, Tumor , Cell Movement , Humans , Kaplan-Meier Estimate , Lung Neoplasms/secondary , Male , Mice, Inbred BALB C , Receptors, Vasoactive Intestinal Polypeptide, Type I/genetics , Stomach Neoplasms/metabolism , TRPV Cation Channels/genetics , Vasoactive Intestinal Peptide/metabolism , Xenograft Model Antitumor AssaysABSTRACT
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 development. CaSR expression was enhanced in gastric cancer specimens, which positively correlated with serum calcium concentrations, tumor progression, poor survival, and male gender in gastric cancer patients. CaSR and transient receptor potential cation channel subfamily V member 4 (TRPV4) were colocalized in gastric cancer cells, and CaSR activation evoked TRPV4-mediated Ca2+ entry. Both CaSR and TRPV4 were involved in Ca2+-induced proliferation, migration, and invasion of gastric cancer cells through a Ca2+/AKT/ß-catenin relay, which occurred only in gastric cancer cells or normal cells overexpressing CaSR. Tumor growth and metastasis of gastric cancer depended on CaSR in nude mice. Overall, our findings indicate that calcium may enhance expression and function of CaSR to potentially promote gastric cancer, and that targeting the novel CaSR/TRPV4/Ca2+ pathway might serve as preventive or therapeutic strategies for gastric cancer. Cancer Res; 77(23); 6499-512. ©2017 AACR.
Subject(s)
Calcium/metabolism , Carcinogenesis/pathology , Receptors, Calcium-Sensing/metabolism , Stomach Neoplasms/pathology , TRPV Cation Channels/metabolism , Animals , Cell Cycle/physiology , Cell Line, Tumor , Cell Movement/physiology , Cell Proliferation/physiology , Disease Progression , Humans , Male , Mice , Mice, Nude , Neoplasm Transplantation , Proto-Oncogene Proteins c-akt/metabolism , Rats , Transplantation, Heterologous , beta Catenin/metabolismABSTRACT
Although purinegic signaling is important in regulating gastric physiological functions, it is currently unknown for its role in gastric cancer (GC). We demonstrate for the first time that the expression of P2Y6 receptors was markedly down-regulated in human GC cells and primary GC tissues compared to normal tissues, while the expression of P2Y2 and P2Y4 receptors was up-regulated in GC cells. Moreover, the expression levels of P2Y6 receptors in GC tissues were correlated to tumor size, differentiation, metastasis to lymph nodes, and the survival rate of the patients with GC. Ncleotides activated P2Y6 receptors to raise cytosolic Ca2+ concentrations in GC cells through store-operated calcium entry (SOCE), and then mediated Ca2+-dependent inhibition of ß-catenin and proliferation, eventually leading to GC suppression. Furthermore, UTP particularly blocked the G1/S transition of GC cells but did not induce apoptosis. Collectively, we conclude that nucleotides activate P2Y6 receptors to suppress GC growth through a novel SOCE/Ca2+/ß-catenin-mediated anti-proliferation of GC cells, which is different from the canonical SOCE/Ca2+-induced apoptosis in other tumors.
Subject(s)
Antineoplastic Agents/pharmacology , Calcium Channels/genetics , Gene Expression Regulation, Neoplastic , Receptors, Purinergic P2/genetics , Stomach Neoplasms/drug therapy , Uridine Triphosphate/pharmacology , beta Catenin/genetics , Animals , Calcium/metabolism , Calcium Channels/metabolism , Cell Line, Tumor , Cell Proliferation , Epithelial Cells/drug effects , Epithelial Cells/metabolism , Epithelial Cells/pathology , G1 Phase Cell Cycle Checkpoints/drug effects , G1 Phase Cell Cycle Checkpoints/genetics , Humans , Indoles/pharmacology , Lymphatic Metastasis , Male , Mice , Mice, Nude , Receptors, Purinergic P2/metabolism , Receptors, Purinergic P2Y2/genetics , Receptors, Purinergic P2Y2/metabolism , Signal Transduction , Spiperone/pharmacology , Stomach Neoplasms/genetics , Stomach Neoplasms/metabolism , Stomach Neoplasms/pathology , Survival Analysis , Tumor Burden/drug effects , Uridine Diphosphate/pharmacology , Xenograft Model Antitumor Assays , beta Catenin/metabolismABSTRACT
The calcium sensing receptor (CaSR) is functionally expressed in normal human pancreases, but its pathological role in pancreatic tumorigenesis is currently unknown. We sought to investigate the role of CaSR in pancreatic cancer (PC) and the underlying molecular mechanisms. We revealed that the expression of CaSR was consistently downregulated in the primary cancer tissues from PC patients, which was correlated with tumor size, differentiation and poor survival of the patients. CaSR activation markedly suppressed pancreatic tumorigenesis in vitro and in vivo likely through the Ca(2+) entry mode of Na(+)/Ca(2+) exchanger 1 (NCX1) to induce Ca(2+) entry into PC cells. Moreover, NCX1-mediated Ca(2+) entry resulted in Ca(2+)-dependent inhibition of ß-catenin signaling in PC cells, eventually leading to the inhibition of pancreatic tumorigenesis. Collectively, we demonstrate for the first time that CaSR exerts a suppressive function in pancreatic tumorigenesis through a novel NCX1/Ca(2+)/ß-catenin signaling pathway. Targeting this specific signaling pathway could be a potential therapeutic strategy for PC.
