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Staphylococcus aureus is a noteworthy pathogen in allergic diseases, as four staphylococcal exotoxins activate mast cells, a significant contributor to inflammation, in an IgE‐independent manner. Although the adhesion of mast cells is an essential process for their immune responses, only a small number of exotoxins have been reported to affect the process. Here, we demonstrated that staphylococcal superantigen‐like (SSL) 3, previously identified as a toll‐like receptor 2 agonist, induced the adhesion of murine bone marrow‐derived mast cells to culture substratum. SSL3‐induced adhesion was mediated by fibronectin in an Arg‐Gly‐Asp (RGD) sequence‐dependent manner, suggesting the integrins were involved in the process. Additionally, SSL3 was found to bind to an anti‐adhesive surface protein CD43. SSL3 induced the adhesion of HEK293 cells expressing exogenous CD43, suggesting that CD43 is the target molecule for adhesion induced by SSL3. Evaluation of SSL3‐derived mutants showed that the C‐terminal region (253–326), specifically T285 and H307, are necessary to induce adhesion. SSL3 augmented the IL‐13 production of mast cells in response to immunocomplex and SSL12. These findings reveal a novel function of SSL3, triggering cell adhesion and enhancing mast cell activation. This study would clarify the correlation between S. aureus and allergic diseases such as atopic dermatitis. [ABSTRACT FROM AUTHOR]

The inflammatory bowel disease ulcerative colitis (UC) frequently progresses to colon cancer. To understand the mechanisms by which UC patients develop colon carcinomas, we used a mouse model of the disease whereby administration of azoxymethane (AOM) followed by repeated dextran sulfate sodium (DSS) ingestion causes severe colonic inflammation and the subsequent development of multiple tumors. We found that treating WT mice with AOM and DSS increased TNF-[alpha] expression and the number of infiltrating leukocytes expressing its major receptor, p55 (TNF-Rp55), in the lamina propria and submucosal regions of the colon. This was followed by the development of multiple colonic tumors. Mice lacking TNF-Rp55 and treated with AOM and DSS showed reduced mucosal damage, reduced infiltration of macrophages and neutrophils, and attenuated subsequent tumor formation. WT mice transplanted with TNF-Rp55-deficient bone marrow also developed significantly fewer tumors after AOM and DSS treatment than either WT mice or TNF-Rp55-deficient mice transplanted with WT bone marrow. Furthermore, administration of etanercept, a specific antagonist of TNF-[alpha], to WT mice after treatment with AOM and DSS markedly reduced the number and size of tumors and reduced colonic infiltration by neutrophils and macrophages. These observations identify TNF-[alpha] as a crucial mediator of the initiation and progression of colitis-associated colon carcinogenesis and suggest that targeting TNF-[alpha] may be useful in treating colon cancer in individuals with UC., Introduction Ulcerative colitis (UC) is an inflammatory bowel disease characterized by pathological mucosal damage and ulceration, which can involve the rectum and extend proximally (1). The incidence of UC in [...]

Biomarkers for early diagnosis of pancreatic cancer are greatly needed, as the high fatality of this cancer is in part due to delayed detection. α1,4‐linked N‐acetylglucosamine (αGlcNAc), a unique O‐glycan specific to gastric gland mucus, is biosynthesized by α1,4‐N‐acetylglucosaminyltransferase (α4GnT) and primarily bound at the terminal glycosylated residue to scaffold protein MUC6. We previously reported that αGlcNAc expression decreases at early stages of neoplastic pancreatic lesions, followed by decreased MUC6 expression, although functional effects of these outcomes were unknown. Here, we ectopically expressed α4GnT, the αGlcNAc biosynthetic enzyme, together with MUC6 in the human pancreatic cancer cell lines MIA PaCa‐2 and PANC‐1, neither of which expresses α4GnT and MUC6. We observed significantly suppressed proliferation in both lines following coexpression of α4GnT and MUC6. Moreover, cellular motility decreased following MUC6 ectopic expression, an effect enhanced by cotransduction with α4GnT. MUC6 expression also attenuated invasiveness of both lines relative to controls, and this effect was also enhanced by additional α4GnT expression. We found αGlcNAc‐bound MUC6 formed a complex with trefoil factor 2. Furthermore, analysis of survival curves of patients with pancreatic ductal adenocarcinoma using a gene expression database showed that samples marked by higher A4GNT or MUC6 mRNA levels were associated with relatively favorable prognosis. These results strongly suggest that αGlcNAc and MUC6 function as tumor suppressors in pancreatic cancer and that decreased expression of both may serve as a biomarker of tumor progression to pancreatic cancer. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the expression of annexin A1 protein in patients with renal cell carcinoma. Methods: Annexin A1 expression was examined in renal cell carcinoma specimens from 27 patients, and their disease‐free survival was analyzed using the log–rank test. Annexin A1 knockdown in the human renal cell carcinoma cell line Caki‐1 was carried out, and its proliferation, invasion, motility and adhesion were compared with those of control cells. Results: In 13 out of 27 patients, annexin A1 was highly expressed in the membrane of renal cell carcinoma tumor cells, whereas in the rest of the patients, annexin A1 expression was weak or negligible in the membrane of those cells. Patients with high annexin A1 expression had significantly poorer disease‐free survival than those with weak or negligible annexin A1 expression (P = 0.031). In the renal cell carcinoma cell line, annexin A1 knockdown cells showed significantly decreased proliferation, invasion, motility and adhesion relative to control cells, and expressed lower relative levels of membrane‐type 1 matrix metalloproteinase and hypoxia‐inducible factor 1‐alpha transcripts, showing a potential pathway regulated by annexin A1. Conclusion: Annexin A1 is associated with renal cell carcinoma malignant potential and could serve as a marker of poor prognosis. [ABSTRACT FROM AUTHOR]

Pim-3, a member of the proto-oncogene Pim family with serine/threonine kinase activity was aberrantly expressed in cancerous lesions of endoderm-derived organs such as liver, pancreas, and colon. The aim of this study was to clarify the role of Pim-3 expression in the tumorigenesis and the development of gastric carcinomas. Pim-3 expression was immunohistochemically examined on the tissue microarrays containing primary ( n = 285) and metastastic ( n = 37) sites of gastric carcinomas, in comparison with adenoma ( n = 48) and non-cancerous mucosa ( n = 84). It was also compared with the clinicopathological parameters of gastric carcinomas. Pim-3 expression was enhanced in adenoma (64.6%) and metastasis sites of gastric carcinoma (73.0%), to a lesser degree in primary sites of gastric carcinoma (39.3%) when compared to non-cancerous mucosa (13.1%, p < 0.0001). Pim-3 expression levels were higher in intestinal-type than diffuse-type gastric carcinoma ( p = 0.018). Pim-3 expression was closely correlated with sex ( p = 0.047), lymphatic ( p = 0.019) and venous invasion ( p = 0.014). Pim-3 expression was correlated significantly with vascular endothelial growth factor (VEGF, p = 0.009) and extracellular matrix metalloproteinase inducer (EMMPRIN, p = 0.032), both of which are presumed to be involved in neovascularization, a crucial step for metastasis. On the contrary, phosphatase and tensin homology deleted from human chromosome 10 (Pten) negative gastric carcinomas exhibited higher Pim-3 expression than Pten positive ones ( p = 0.042). There was no relationship between Pim-3 expression and MVD in gastric carcinomas ( p = 0.715). Furthermore, patients with Pim-3 positive gastric cancer, showed a lower cumulative survival rate than those with Pim-3 negative gastric cancer ( p = 0.014) and Pim-3 positive was also identified as an independent prognostic factor for gastric carcinoma patients ( p = 0.006). Aberrant Pim-3 expression was involved in gastric adenoma–adenocarcinoma sequence and subsequent invasion and metastasis process in gastric cancer. Moreover, Pim-3 may be employed to predict the prognosis of gastric cancer patients. Distinct Pim-3 expression underlies the molecular mechanisms for the differentiation of intestinal-type and diffuse-type carcinomas. [ABSTRACT FROM AUTHOR]