MSK1基因启动子去甲基化用于预测KRAS突变型肠癌患者术后复发时间的诊断标志物研究及其去甲基化机理研究

批准号:
81971999
项目类别:
面上项目
资助金额:
55.0 万元
负责人:
傅新晖
依托单位:
学科分类:
分子生物学检验
结题年份:
2023
批准年份:
2019
项目状态:
已结题
项目参与者:
傅新晖
国基评审专家1V1指导 中标率高出同行96.8%
结合最新热点,提供专业选题建议
深度指导申报书撰写,确保创新可行
指导项目中标800+,快速提高中标率
微信扫码咨询
中文摘要
我们发现中国肠癌患者中KRAS突变者占比高达47%(IJC,2019),其化疗效果差,易复发。已知MSK1参与促癌和肿瘤耐药。经确认MSK1仅在KRAS突变型肠癌细胞中上调 (DLD,2017),但机制不明。MSK1启动子区含有可结合缺氧诱导因子HIFs的缺氧反应元件(HRE),且预实验证实缺氧时,MSK1启动子在KRAS突变型肠癌细胞HCT116中去甲基化,但在野生型肠癌细胞Caco2中高甲基化。据此提出:缺氧诱导突变细胞上调去甲基化酶,如TET1,使MSK1启动子去甲基化后形成适合HIFs与HRE结合的空间构象,促进转录。另,前期小样本数据提示:联合MSK1去甲基化指标,可更精确预测KRAS突变型患者复发时间。本项目拟利用5495例肠癌队列探索其诊断价值;研究缺氧时HCT116中的HIFs-TET1-MSK1通路及靶向该通路逆转化疗耐药的可行性,为KRAS突变型肠癌的复发干预提供依据。
英文摘要
We found 47% colorectal cancer patients carry KRAS mutations. KRAS mutant patients have poor effect of chemotherapy and shorter time to recurrence. MSK1 is known to be involved in carcinogenisis and chemotherapy resisitance. Also, we found MSK1 only overexpressed in KRAS mutant CRC cells. However, the underlying mechanism of its upregulation is unclear. Unveiling this mechanism will falicitate the developing of new therapy for KRAS mutant CRC patients. In our preliminary data, MSK1’s promoter is demethylated in HCT116 cells but methylated in Caco2 cells. A HRE element was also found in MSK1’s promoter, which can bind to HIFs. Because hypoxia prevails on solid tumors, we proposed our hypothesis: hypoxia can induce some demethylase, such as TET1, which can demethylate the promoter of MSK1 and enhance the binding ability of HIFs and consequently activating the expression of MSK1. Moreover, data from a small cohort indicated that MSK1’s demethylation is a potential marker for more precise prediction of time to recurrence of KRAS mutant CRC patients. So we will evaluate the diagnosis value of MSK1’s promoter demethylation with our established 5495 CRC cohort. And study the HIFs-TET1-MSK1 pathway in HCT116 cells under hypoxic conditions. Thus, our study will provide new insights for the relapse interference of KRAS mutant CRC patients.
期刊论文列表
专著列表
科研奖励列表
会议论文列表
专利列表
DOI:10.3389/fonc.2021.595675
发表时间:2021
期刊:Frontiers in oncology
影响因子:4.7
作者:Fu X;Lin H;Fan X;Zhu Y;Wang C;Chen Z;Tan X;Huang J;Cai Y;Huang Y
通讯作者:Huang Y
p-MSK1 (Thr581)影响结直肠癌预后的机制研究
- 批准号:81201545
- 项目类别:青年科学基金项目
- 资助金额:23.0万元
- 批准年份:2012
- 负责人:傅新晖
- 依托单位:
国内基金
海外基金
