The stem cell ubiquitin ligase RNF43 in gastric homeostasis, DNA damage response and carcinogenesis: from biological function to application as biomarker

胃癌是全球癌症相关死亡的第三大原因，由于转移、复发和治疗选择不足，所有阶段的5年生存率仍然很低（约20%）。环指泛素连接酶RNF43最初被描述为结直肠癌中的肿瘤抑制因子，已发现在胃癌中频繁突变，并且在呈现微卫星不稳定性（MSI）的肿瘤中显示高达54%的截短突变的高倾向性。最近，RNF43已被证明与p53相互作用，并假设RNF43与DNA损伤反应之间可能存在联系。因此，RNF43可能参与对化疗或放疗的反应，并且突变可能代表胃癌管理和患者分层的有趣标记。基于一些初步的数据支持这样的假设，在本项目中，我们建议分析内源性RNF43在体外和体内的胃细胞中的功能，通过敲除或过表达突变的RNF43在细胞系以及在小鼠中。我们已经产生了携带RNF43点突变或缺失的小鼠，这将在本项目中进行彻底的表征。鉴于胃癌多发生于慢性H. pylori感染，我们计划研究RNF43在H.幽门感染最后，我们建议使用癌细胞系以及来自正常胃和患者胃肿瘤样本的类器官来评估RNF43状态是否影响胃肿瘤对化疗或放疗的反应性。总之，我们的数据可能有助于建立RNF43突变状态分析作为选择治疗方案治疗胃癌患者的工具

Gastric cancer is the third leading cause of cancer-related deaths worldwide, and the 5-year survival rate across all stages is still low (around 20%) due to metastasis, recurrence and insufficient therapeutical options. The ring finger ubiquitin ligase RNF43, initially described as a tumor suppressor in colorectal cancer, has been found to be frequently mutated in gastric cancer and showed high proclivity for truncating mutations of up to 54% in tumours presenting with microsatellite instability (MSI). Recently, RNF43 has been shown to interact with p53, and a possible link between RNF43 and DNA damage response was postulated. Thus, RNF43 might be involved in the response to chemotherapy or radiation, and mutations might represent an interesting marker for gastric cancer management and patient stratification. Based on several preliminary data which support such assumption, in the current project we propose to analyse the function of endogenous RNF43 in gastric cells in vitro and in vivo by knocking out or overexpressing mutated RNF43 in cell lines as well as in mice. We have already generated mice bearing RNF43 point mutations or deletions, which will be thoroughly characterized in this project. Given the fact that gastric cancer mostly arises upon chronic H. pylori infection, we are planning to investigate the function of RNF43 in the context of H. pylori infection. Finally, we propose to assess whether RNF43 status influences the responsiveness of gastric tumors towards chemotherapy or radiation using cancer cell lines as well as organoids from normal stomach and gastric tumour samples of patients. In summary, our data may help to establish the analysis of RNF43 mutation status as a tool for the selection of therapeutic regimens to treat gastric cancer patients