Inflammation-induced repression of tumor suppressor miR-7 in gastric tumor cells.

Inflammation has an important role in cancer development through various mechanisms. It has been shown that dysregulation of microRNAs (miRNAs) that function as oncogenes or tumor suppressors contributes to tumorigenesis. However, the relationship between inflammation and cancer-related miRNA expression in tumorigenesis has not yet been fully understood. Using K19-C2mE and Gan mouse models that develop gastritis and gastritis-associated tumors, respectively, we found that 21 miRNAs were upregulated, and that 29 miRNAs were downregulated in gastric tumors in an inflammation-dependent manner. Among these miRNAs, the expression of miR-7, a possible tumor suppressor, significantly decreased in both gastritis and gastric tumors. Moreover, the expression of miR-7 in human gastric cancer was inversely correlated with the levels of interleukin-1ß and tumor necrosis factor-α, suggesting that miR-7 downregulation is related to the severity of inflammatory responses. In the normal mouse stomach, miR-7 expression was at a basal level in undifferentiated gastric epithelial cells, and was induced during differentiation. Moreover, transfection of a miR-7 precursor into gastric cancer cells suppressed cell proliferation and soft agar colony formation. These results suggest that suppression of miR-7 expression is important for maintaining the undifferentiated status of gastric epithelial cells, and thus contributes to gastric tumorigenesis. Although epigenetic changes were not found in the CpG islands around miR-7-1 of gastritis and gastric tumor cells, we found that activated macrophage-derived small molecule(s) (<3 kDa) are responsible for miR-7 repression in gastric cancer cells. Furthermore, the miR-7 expression level significantly decreased in the inflamed gastric mucosa of Helicobacter-infected mice, whereas it increased in the stomach of germfree K19-C2mE and Gan mice wherein inflammatory responses were suppressed. Taken together, these results indicate that downregulation of tumor suppressor miR-7 is a novel mechanism by which the inflammatory response promotes gastric tumorigenesis.

CDX2 expression in the stomach with intestinal metaplasia and intestinal-type cancer: Prognostic implications.

CDX2, a transcriptional factor expressed in the intestine, is implicated in the development and maintenance of the intestinal mucosa. Recent studies have demonstrated that CDX2 is expressed in the intestinal metaplasia of the stomach and intestinal-type gastric cancer, while it is not expressed in the normal gastric mucosa. To investigate the role of CDX2 in gastric cancer, we determined CDX2 expression and cell proliferation rate in various types of gastric cancer tissues by immunostaining. Surgically dissected gastric cancer tissues were collected from 40 patients. Consistent with previous reports, CDX2 was expressed in most gastric mucosa samples with intestinal metaplasia (89%, 16/18), although it was not found in the adjacent normal mucosa. CDX2 expression was also detected in 64% (18/28) of intestinal-type gastric cancer cases, whereas it was not observed in the diffuse-type gastric cancer (0/12). Moreover, the CDX2-positive gastric cancer samples showed significantly lower index for Ki-67 immunostaining, indicating reduced cell proliferation rates than in the CDX2-negative samples. Importantly, multivariate analysis for the overall survival rate revealed that the CDX2-positive gastric cancer patients survived significantly longer than the CDX2-negative patients. Even among the intestinal-type gastric cancer cases, the CDX2-positive group showed a lower Ki-67 index and longer postoperative survival than the CDX2-negative group. These results collectively indicate that CDX2 expression in gastric cancer tissues can be a novel prognostic marker for patient survival.

Mapping of the genes encoding mouse prostaglandin D, E, and F and prostacyclin receptors.

Prostaglandins and prostacyclin are metabolites of arachidonic acid and exert a variety of actions to maintain local homeostasis in the body. Their actions are mediated by cell surface receptors specific to the respective ligands. Using a panel of interspecific back-cross mice, we have mapped the prostaglandin D receptor gene (Ptgdr), prostaglandin E receptor subtype EP(1) gene (Ptgerepl), prostaglandin F receptor gene (Ptgfr), and prostacyclin receptor gene (Ptgir). Ptgdr mapped to proximal Chr 14, Ptgfr mapped to distal Chr 3, Ptgerepl mapped to middle Chr 8, and Ptgir mapped to proximal Chr 7.