Helicobacter pylori (H. pylori) infection is strongly associated with the development of gastric diseases but also with several extragastric diseases. The clinical outcomes caused by H. pylori infection are considered to be associated with a complex combination of host susceptibility, environmental factors and bacterial isolates. Infections involving H. pylori strains that possess the virulence factor CagA have a worse clinical outcome than those involving CagA-negative strains. It is remarkable that CagA-positive H. pylori increase the risk for gastric cancer over the risk associated with H. pylori infection alone. CagA behaves as a bacterial oncoprotein playing a key role in H. pylori-induced gastric cancer. Activation of oncogenic signaling pathways and inactivation of tumor suppressor pathways are two crucial events in the development of gastric cancer. CagA shows the ability to affect the expression or function of vital protein in oncogenic or tumor suppressor signaling pathways via several molecular mechanisms, such as direct binding or interaction, phosphorylation of vital signaling proteins and methylation of tumor suppressor genes. As a result, CagA continuously dysregulates of these signaling pathways and promotes tumorigenesis. Recent research has enriched our understanding of how CagA effects on these signaling pathways. This review summarizes the results of the most relevant studies, discusses the complex molecular mechanism involved and attempts to delineate the entire signaling pathway.

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/β-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.

The MiT/TFE transcription factors play a pivotal role in the regulation of autophagy and lysosomal biogenesis. The subcellular localization and activity of MiT/TFE proteins are primarily regulated through phosphorylation. And the phosphorylated protein is retained in the cytoplasm and subsequently translocates to the nucleus upon dephosphorylation, where it stimulates the expression of hundreds of genes, leading to lysosomal biogenesis and autophagy induction. The transcription factor-mediated lysosome-to-nucleus signaling can be directly controlled by several signaling molecules involved in the mTORC1, PKC, and AKT pathways. MiT/TFE family members have attracted much attention owing to their intracellular clearance of pathogenic factors in numerous diseases. Recently, multiple studies have also revealed the MiT/TFE proteins as master regulators of cellular metabolic reprogramming, converging on autophagic and lysosomal function and playing a critical role in cancer, suggesting that novel therapeutic strategies could be based on the modulation of MiT/TFE family member activity. Here, we present an overview of the latest research on MiT/TFE transcriptional factors and their potential mechanisms in cancer.

ATP is an abundant biochemical component of the tumor microenvironment and a physiologic ligand for the P2Y₂ nucleotide receptor (P2Y₂R). In this study, we investigated the effect of ATP on the cellular behavior of human hepatocellular carcinoma (HCC) cells and the role of P2Y₂R in ATP action and aimed to find a new therapeutic target against HCC. The experiments were performed in native isolated human HCC cells, normal hepatocytes, human HCC cell lines, and nude mice. We found that the mRNA and protein expression levels of P2Y₂R in native human HCC cells and the human HCC cell lines HepG2 and BEL-7404 were enhanced markedly compared with human normal hepatocytes and the normal hepatocyte line LO2, respectively. ATP induced intracellular Ca²⁺ increases in HCC cells and promoted the proliferation and migration of HCC cells and the growth of HCC in nude mice. The P2Y receptor antagonist suramin, P2Y₂R-specific shRNA, the store-operated calcium channel inhibitors 2-aminoethoxydiphenyl borate (2-APB) and 1-(β-3-(4-methoxy-phenyl) propoxyl-4-methoxyphenethyl)1H-imidazole-hydrochloride (SKF96365), and stromal interaction molecule (STIM1)-specific shRNA inhibited the action of ATP on HCC cells. In conclusion, P2Y₂R mediated the action of ATP on the cellular behavior of HCC cells through store-operated calcium channel-mediated Ca²⁺ signaling, and targeting P2Y₂R may be a promising therapeutic strategy against human HCC.

We recently reported that transforming growth factor-β (TGF-β) induces an increase in cytosolic Ca²⁺ ([Ca²⁺]_cyt) in pancreatic cancer cells, but the mechanisms by which TGF-β mediates [Ca²⁺]_cyt homeostasis in these cells are currently unknown. Transient receptor potential (TRP) channels and Na⁺/Ca²⁺ exchangers (NCX) are plasma membrane proteins that play prominent roles in controlling [Ca²⁺]_cyt homeostasis in normal mammalian cells, but little is known regarding their roles in the regulation of [Ca²⁺]_cyt in pancreatic cancer cells and pancreatic cancer development. Expression and function of NCX1 and TRPC1 proteins were characterized in BxPc3 pancreatic cancer cells. TGF-β induced both intracellular Ca²⁺ release and extracellular Ca²⁺ entry in these cells; however, 2-aminoethoxydiphenyl borate [2-APB; a blocker for both inositol 1,4,5-trisphosphate (IP₃) receptor and TRPC], LaCl₃ (a selective TRPC blocker), or KB-R7943 (a selective inhibitor for the Ca²⁺ entry mode of NCX) markedly inhibited the TGF-β-induced increase in [Ca²⁺]_cyt. 2-APB or KB-R7943 treatment was able to dose-dependently reverse membrane translocation of PKCα induced by TGF-β. Transfection with small interfering RNA (siRNA) against NCX1 almost completely abolished NCX1 expression in BxPc3 cells and also inhibited PKCα serine phosphorylation induced by TGF-β. Knockdown of NCX1 or TRPC1 by specific siRNA transfection reversed TGF-β-induced pancreatic cancer cell motility. Therefore, TGF-β induces Ca²⁺ entry likely via TRPC1 and NCX1 and raises [Ca²⁺]_cyt in pancreatic cancer cells, which is essential for PKCα activation and subsequent tumor cell invasion. Our data suggest that TRPC1 and NCX1 may be among the potential therapeutic targets for pancreatic cancer.

Because human duodenal mucosal bicarbonate secretion (DMBS) protects duodenum against acid-peptic injury, we hypothesize that estrogen stimulates DMBS, thereby attributing to the clinically observed lower incidence of duodenal ulcer in premenopausal women than the age-matched men. We found that basal and acid-stimulated DMBS responses were 1.5 and 2.4-fold higher in female than male mice in vivo, respectively. Acid-stimulated DMBS in both genders was abolished by ICI 182,780 and tamoxifen. Estradiol-17β (E₂) and the selective estrogen receptor (ER) agonists of ERα [1,3,5-Tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole] and ERβ [2,3-bis(4-hydroxyphenyl) propionitrile], but not progesterone, rapidly stimulated ER-dependent murine DMBS in vivo. E₂ dose dependently stimulated murine DMBS, which was attenuated by a Cl⁻/HCO₃⁻ anion exchanger inhibitor 4,4′-didsothio- cyanostilbene-2, 2′-disulfonic acid, removal of extracellular Cl⁻, and in cystic fibrosis transmembrane conductance regulator knockout female mice. E₂ stimulated murine DMBS in vitro in both genders with significantly greater response in female than male mice (female to male ratio = 4.3). ERα and ERβ mRNAs and proteins were detected in murine duodenal epithelium of both genders; however, neither ERα nor ERβ mRNA and protein expression levels differed according to gender. E₂ rapidly mobilized intracellular calcium in a duodenal epithelial SCBN cell line that expresses ERα and ERβ, whereas BAPTA-AM abolished E₂-stimulated murine DMBS. Thus, our data show that E₂ stimulates DMBS via ER dependent mechanisms linked to intracellular calcium, cystic fibrosis transmembrane conductance regulator, and Cl⁻/HCO₃⁻ anion exchanger. Gender-associated differences in basal, acid- and E₂-stimulated DMBS may have offered a reasonable explanation for the clinically observed lower incidence of duodenal ulcer in premenopausal women than age-matched men.