PubMed · 16097243
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Robert J Isaacson. 2005. Mostly for men.. https://doi.org/10.1043/0003-3219(2005)75%5B694%3Amfm%5D2.0.co%3B2
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Intake of salt and salty food is known as a risk factor for gastric carcinogenesis. To examine the dose-dependence and the mechanisms underlying enhancing effects, Mongolian gerbils were treated with N-methyl-N-nitrosourea (MNU), Helicobacter pylori and food containing various concentrations of salt, and were sacrificed after 50 weeks. Among gerbils treated with MNU and H. pylori, the incidences of glandular stomach cancers were 15% in the normal diet group and 33%, 36% and 63% in the 2.5%, 5% and 10% NaCl diet groups, showing dose-dependent increase (p < 0.01). Intermittent intragastric injection of saturated NaCl solution, in contrast, did not promote gastric carcinogenesis. In gerbils infected with H. pylori, a high salt diet was associated with elevation of anti-H. pylori antibody titers, serum gastrin levels and inflammatory cell infiltration in a dose-dependent fashion. Ten percent NaCl diet upregulated the amount of surface mucous cell mucin (p < 0.05), suitable for H. pylori colonization, despite no increment of MUC5AC mRNA, while H. pylori infection itself had an opposing effect, stimulating transcription of MUC6 and increasing the amount of gland mucous cell mucin (GMCM). High salt diet, in turn, decreased the amount of GMCM, which acts against H. pylori infection. In conclusion, the present study demonstrated dose-dependent enhancing effects of salt in gastric chemical carcinogenesis in H. pylori-infected Mongolian gerbils associated with alteration of the mucous microenvironment. Reduction of salt intake could thus be one of the most important chemopreventive methods for human gastric carcinogenesis.
We quantified the expression of survivin, both as mRNA in real-time PCR and protein in immunohistochemistry, in tumor samples of 112 patients with esophageal cancer (56 squamous cell carcinomas and 56 adenocarcinomas). Overall survival of squamous cell carcinoma patients with high survivin mRNA levels was significantly less than that of patients with low survivin mRNA levels (p = 0.0033). Distribution pattern of survivin (nuclear vs. cytoplasmic or mixed) was not correlated to survival, while the extent of immunostaining was significantly correlated to survivin mRNA values (p = 0.016) and had prognostic relevance in univariate analysis (p = 0.0012). Cox's proportional-hazard regression model showed that tumor survivin expression in esophageal squamous cell carcinoma was the most important prognostic factor, independent of tumor stage and other histopathological factors, both as mRNA relative value (p = 0.0259) and protein immunostaining (p = 0.0147). In esophageal adenocarcinoma, survivin expression and pattern of distribution had no prognostic relevance. Thus, quantifying survivin expression provides a prognostic marker only for esophageal squamous tumors.
Infection with cagA-positive Helicobacter pylori (H. pylori) is associated with the development of gastric adenocarcinoma. The cagA gene product CagA is delivered from the bacterium into the cytoplasm of the bacterium-attached gastric epithelial cell via the type-IV secretion system. Upon membrane localization and subsequent tyrosine phosphorylation by Src family kinases, translocated CagA functions as a scaffolding adaptor that interacts with a number of host proteins involved in cell signaling in both tyrosine phosphorylation-dependent and -independent manners. Of special interest is the interaction of CagA with the SHP-2 tyrosine phosphatase, of which gain-of-function mutations have recently been found in human malignancies. Through the complex formation, SHP-2 is catalytically activated and induces morphological transformation that is associated with increased cell motility. In addition to the perturbation of intracellular signaling, CagA disrupts the apical junctional complex that regulates the cell-cell contact and maintains the integrity of the epithelial structure. These CagA activities may collectively cause cellular dysfunctions that promote accumulation of multiple genetic changes involved in malignant transformation. Further elucidation of host cell signaling targeted by CagA should provide a new paradigm for 'bacterial carcinogenesis' and also give insights into general understanding of inflammation-mediated cancers. Clinically, detailed studies on the relationship between structural diversity and degree of pathogenic activity of CagA should make it possible to identify a high-risk group for gastric carcinoma among H. pylori-infected populations through cagA genotyping.