Abstract
The E3 ubiquitin ligase ring finger protein 43 (RNF43) is frequently mutated in gastric tumors and loss of RNF43 expression was suggested to be one of the key events during the transition from adenoma to gastric carcinoma. Functional studies on RNF43 have shown that it acts as a tumor suppressor by negatively regulating Wnt signaling. Interestingly, we observed that RNF43H292R/H295R mice bearing two point mutations in the ring domain displayed thickening of the mucosa at early age but did not develop neoplasia. In this study, we infected these mice for 6 months with Helicobacter pylori, which has been described as one of the major risk factors for gastric cancer. Mice bearing mutant RNF43H292R/H295R showed higher gastritis scores upon H. pylori infection compared to wild-type mice, accompanied by increased lymphocyte infiltration and Ifng levels. Furthermore, infected Rnf43 mutant mice developed atrophy, hyperplasia and MUC2 expressing metaplasia and displayed higher levels of the gastric stem cell marker CD44 and canonical NF-κB signaling. In summary, our results show that transactivating mutations in the tumor suppressor Rnf43 can worsen H. pylori induced pathology.
Highlights
Gastric cancer has been described as a multifactorial disease with high interindividual and intraindividual heterogeneity [1]
Our results show that H. pylori infection worsens gastric pathology of RNF43H292R/H295R mice and suggest that ring finger protein 43 (RNF43) mutations in combination with sustained chronic inflammation contribute to the development of gastric malignancies
To further characterize the immune response of RNF43H292R/H295R mice compared to wild-type mice towards H. pylori infection, we analyzed the expression of different cytokines typically induced
Summary
Gastric cancer has been described as a multifactorial disease with high interindividual and intraindividual heterogeneity [1]. Much effort has been applied to define molecular signatures that may be useful in classifying and developing targeted therapeutic approaches for gastric cancer patients. To this end, analysis of the mutational landscape of gastric cancer has allowed generation of better molecular classifications and the definition of important genes driving gastric carcinogenesis. Analysis of the mutational landscape of gastric cancer has allowed generation of better molecular classifications and the definition of important genes driving gastric carcinogenesis In this context, the E3 ubiquitin ligase ring finger protein 43 (RNF43) was found to be frequently mutated in gastric tumors [2,3,4] highlighting an important role for RNF43 in gastric carcinogenesis. RNF43 downregulation in gastric tumors was associated with metastasis, TNM staging and poor survival [7], suggesting that loss of RNF43 function is one of the key events in gastric carcinogenesis
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