泛素特异性蛋白酶USP43调控HDAC11\IL-10促进炎症性肠病与肠炎-癌转化的作用及机制研究

The incidence of inflammatory bowel disease is increasing year by year. Chronic colitis significantly increases the risk of colon cancer. To find the key molecular and relative molecular mechanisms controlling inflammatory bowel disease will be determined. Deubiquitination enzymes play an important role in the regulation of protein stability and activity through deubiquitination. However, the function and regulation mechanism of deubiquitination enzymes in inflammatory bowel disease are little known. Through bioinformatics analysis, we found that the expression of ubiquitin specific protease USP43 was significantly up-regulated in the pathological tissue of inflammatory bowel disease. Preliminary experiments showed that USP43 knockdown reduced DSS-induced colitis and number of colon tumor induced by AOM\DSS in mice. IL-10 in serum increased significantly in DSS-induced USP43 knockout mice compared with wild type mice. Histone deacetylase HDAC11 can negatively regulate the expression of IL-10, preliminary experiments showed that USP43 can interacts and promotes the stability of HDAC11, suggesting that USP43 may regulate HDAC11\IL-10 to promote the colitis and cancer transformation. The purpose of this study is to investigate the role of USP43 in mouse colitis and colitis-cancer transformation and underlying the molecular mechanism, so as to provide new ideas for the prevention and treatment of inflammatory diseases such as inflammatory bowel disease.

炎症性肠病的发病率逐年升高，长期的肠炎显著增加肠癌的患病风险，明确炎症性肠病发病及调控机理成为该研究中的重点。去泛素化酶通过去泛素化作用调控蛋白的稳定性及活性参与炎症反应，然而去泛素化酶在炎症性肠病中的功能及调控机制研究较少。通过生物信息学分析，我们发现泛素特异性蛋白酶USP43在炎性肠病病理组织中显著上调表达。预实验显示USP43敲除减轻小鼠DSS诱导的肠炎症状且AOM\DSS诱导产生的肠炎相关结肠肿瘤的数量明显减少；在DSS诱导的USP43敲除小鼠血清中IL-10显著增多；组蛋白去乙酰化酶HDAC11可负调控IL-10表达，前期实验显示USP43可结合并促进HDAC11的稳定性，提示USP43可能通过调控HDAC11\IL-10促进肠炎及肠炎-癌转化。本课题拟研究USP43在小鼠肠炎及肠炎-癌转化中的作用及相关分子机制，为炎症性肠病等非可控性炎症疾病的防治提供新思路。

炎症性肠病的发病率逐年升高，长期的肠炎显著增加肠癌的患病风险，明确炎症性肠病发病及调控机理成为该研究中的重点。去泛素化酶通过去泛素化作用调控蛋白的稳定性及活性参与炎症反应及炎癌转化。通过生物信息学分析，我们发现泛素特异性蛋白酶USP43在炎性肠病病理组织中显著上调表达。本项目通过构建基因敲除小鼠，进行小鼠结肠炎-癌建模，观察USP43在小鼠肠炎及肠炎相关肠癌发生发展中的调控作用，结果证实USP43可促进DSS诱导的肠炎及AOM\DSS诱导的肠癌发生，在DSS诱导的USP43敲除小鼠血清中IL-10显著增多。项目重点研究了USP43在促炎症和炎-癌转化中的作用机制。IL-10具有负调控功能，在炎症性肠病中发挥保护作用，IL-10基因敲除的小鼠可自发产生结肠炎，同时IL-10显著抑制肠炎-癌转化。本研究发现USP43可去泛素化HDAC11进而促进HDAC11蛋白稳定性，而HDAC11通过与IL-10基因启动子远端区域结合而抑制IL-10的转录与表达，从而正向调控DSS诱导的肠炎及AOM\DSS诱导的肠癌；并且证明了HDAC11敲除或HDAC11抑制剂具有抑制DSS诱导的肠炎及AOM\DSS诱导的肠癌发生。该研究明确了USP43在肠炎与炎-癌转化中的调控作用及其调控HDAC11的分子机制，为深入了解与寻找肠炎与炎-癌转化治疗靶点提供新思路。

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