Mutated Rnf43 Aggravates Helicobacter Pylori-Induced Gastric Pathology
Mutated Rnf43 Aggravates Helicobacter Pylori-Induced Gastric Pathology
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DOI：
10.3390/cancers11030372
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发表时间：
2019-03-01
期刊：
影响因子：
5.2
通讯作者：
Mejias-Luque, Raquel
中科院分区：
文献类型：
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作者：
Neumeyer, Victoria;Vieth, Michael;Mejias-Luque, Raquel
E3 泛素连接酶环指蛋白 43 (RNF43) 在胃肿瘤中经常发生突变，RNF43 表达缺失被认为是从腺瘤转变为胃癌期间的关键事件之一。 RNF43 的功能研究表明，它通过负向调节 Wnt 信号传导发挥肿瘤抑制因子的作用。有趣的是，我们观察到环结构域带有两个点突变的RNF43(H292R)(/)(H295R)小鼠在早期表现出粘膜增厚，但没有发生肿瘤。在这项研究中，我们用幽门螺杆菌感染这些小鼠 6 个月，幽门螺杆菌被认为是胃癌的主要危险因素之一。与野生型小鼠相比，携带突变体 RNF43(H292R)(/)(H295R) 的小鼠在幽门螺杆菌感染后表现出更高的胃炎评分，并伴有淋巴细胞浸润和 Ifng 水平增加。此外，受感染的 Rnf43 突变小鼠出现萎缩、增生和表达 MUC2 的化生，并表现出更高水平的胃干细胞标记物 CD44 和典型的 NF-κ B 信号传导。总之，我们的结果表明肿瘤抑制因子 Rnf43 的反式激活突变可以恶化幽门螺杆菌诱导的病理。
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 RNF43(H292R)(/)(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 RNF43(H292R)(/)(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-kappa B signaling. In summary, our results show that transactivating mutations in the tumor suppressor Rnf43 can worsen H. pylori induced pathology.