Gastric cancer remains one of the leading causes of global cancer mortality due to therapy resistance, with Helicobacter pylori (H. pylori) infection being a major risk factor. In this study, we report the significance of an elevation of the stem cell regulator SOX9 in bacteria-infected human gastritis and cancer samples, paralleling increased levels of TNFα SOX9 elevation was more intense in specimens containing the pathogenically significant cagA+ strains of H. pylori Notably, we found that SOX9 was required for bacteria-induced gastric cancer cell proliferation, increased levels of β-catenin, and acquisition of stem cell-like properties. Analysis of three large clinical cohorts revealed elevated SOX9 levels in gastric cancer with advanced tumor stage and poor patient survival. Functionally, SOX9 silencing in gastric cancer cells enhanced apoptosis and senescence, concomitantly with a blockade to self-renewal and tumor-initiating capability. Paralleling these effects, we also found SOX9 to mediate cisplatin chemoresistance associated with reduced disease-free survival. Mechanistic interactions between SOX9 and β-catenin expression suggested the existence of a regulatory role for SOX9 targeting the WNT canonical pathway. Taken together, our findings establish the significance of SOX9 in gastric cancer pathobiology and heterogeneity, with implications for targeting WNT-SOX9 signaling as a rational therapeutic strategy. Cancer Res; 76(22); 6735-46. ©2016 AACR.

Diversion colitis occurs commonly in the large bowel remnant after diversion of the fecal stream. Several experimental models of colitis have been described, but none examine the inflammatory alterations that can occur in experimentally defunctioned colons. This characterization could be useful in understanding pathophysiological aspects of diversion colitis, and in developing future therapeutic strategies. Thus, we evaluated the temporal inflammatory alterations in the defunctioned colon of rats by analyzing the histological results, infiltrating neutrophils, pro-inflammatory markers such as cyclooxygenase (COX)-2 and inducible nitric oxide synthase (iNOS), and DNA damage in isolated colonocytes. We compared the obtained data with those from hapten-induced colitis. The experimental diversion of the colon fecal stream induces diversion colitis characterized by an early inflammatory process with increased neutrophil infiltrate, and COX-2 and iNOS expression that resembles, in some aspects, the inflammatory characteristics of chemically induced colitis. After acute inflammation resolution, there was an increase in COX-2 and iNOS expression and the presence of lymphoid follicular hyperplasia and ulcerations, suggesting that diversion colitis can be experimentally established and useful for studying different pathophysiological aspects of this condition.

Inflammatory bowel disease (IBD), Crohn's disease and ulcerative colitis are chronic enteropathies that probably result from a dysregulated mucosal immune response. These pathologies are characterized by oxidative and nitrosative stress, leukocyte infiltration and up-regulation of pro-inflammatory substances. Current IBD treatment presents limitations in both efficacy and safety that stimulated the search for new active compounds. Garcinia cambogia extract has attracted interest due to its pharmacological properties, including gastroprotective effects. In this study, the antiinflammatory activity of a garcinia extract was assessed in TNBS-induced colitis rats. The results obtained revealed that garcinia administration to colitic rats significantly improved the macroscopic damage and caused substantial reductions in increases in MPO activity, COX-2 and iNOS expression. In addition, garcinia extract treatment was able to reduce PGE(2) and IL-1beta colonic levels. These antiinflammatory actions could be related to a reduction in DNA damage in isolated colonocytes, observed with the comet assay. Finally, garcinia extract caused neither mortality nor toxicity signals after oral administration. As such, the antiinflammatory effects provided by the Garcinia cambogia extract result in an improvement of several parameters analysed in experimental colitis and could provide a source for the search for new antiinflammatory compounds useful in IBD treatment.

Our results suggest that infliximab could contribute to the control of intestinal inflammation by modifying adipokine production by mesenteric adipose tissue.