II型乳头状肾癌中延胡索酸水合酶突变调控NK细胞浸润的机制研究
结题报告
批准号:
81972375
项目类别:
面上项目
资助金额:
55.0 万元
负责人:
朱耀
依托单位:
学科分类:
肿瘤免疫治疗
结题年份:
2023
批准年份:
2019
项目状态:
已结题
项目参与者:
朱耀
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中文摘要
II型乳头状肾癌是三大常见的肾癌亚型之一,而恶性程度最高。多组学研究显示II型乳头状肾癌可出现延胡索酸水合酶(FH)突变,同时伴有CpG岛甲基化表型(CIMP)。我们前期数据显示CIMP肿瘤微环境中NK细胞浸润减少,募集NK细胞的特定趋化因子(CX3CL1)过甲基化,而去甲基化药物能抑制CIMP肾癌细胞增殖并上调CX3CL1表达。因此,我们提出“FH突变→CIMP→调控趋化因子→免疫细胞浸润”可能是II型乳头状肾癌进展的重要机制。后续首先验证FH突变是CIMP的驱动因子,基于病例队列构建CIMP特征性分子标记物;探讨CIMP通过甲基化调控趋化因子从而调控免疫细胞浸润的具体机制,在体内和体外环境测试甲基化抑制剂对CIMP相关免疫微环境的影响及机制;最后分析免疫治疗前后采集的标本,明确CIMP和NK的预测价值及肿瘤免疫微环境改变。本研究有助于揭示II型乳头状肾癌进展新机制和治疗新手段。
英文摘要
Type II papillary renal cell carcinoma is one of the three most common kidney cancer subtypes, however, with the highest degree of malignancy. Multi-omics analysis indicated that fumarate hydratase (FH) mutation and a CpG island methylation phenotype (CIMP) could occur in type II papillary renal carcinoma. Our previous data showed a reduced tumor-infiltrating NK cells level and over-methylation of a specific chemokine (CX3CL1) which recruited NK cells in CIMP tumor microenvironment. We also observed that using demethylation drugs could inhibit the proliferation of renal cancer cells with CIMP and up-regulate CX3CL1 expression. Therefore, we proposed a hypothesis: "FH mutation → CIMP → regulation of chemokines → immune cell infiltration". This chain may be an important mechanism for the progression of type II papillary renal carcinoma. Next, we will first examine whether FH mutation is a driving factor of CIMP, and then construct specific molecular markers of CIMP based on multi-cohorts. Then we will explore the certain mechanism that CIMP regulates immune cell infiltration by regulating the methylation level of chemokine genes. In vivo and in vitro experiments will be performed to examine the effect of methylation inhibitors on tumor immune microenvironment, and its mechanism will also be analyzed. Finally, we will collect and analyze paired specimens of type II renal carcinoma to determine the predictive value of CIMP and tumor-infiltrating NK cells for immunotherapy, and also explore changes of tumor immune microenvironment before and after immunotherapy. This study is promising to reveal a new mechanism and propose novel treatment of type II papillary renal cell carcinoma.
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DOI:10.3390/jcm12020623
发表时间:2023-01-12
期刊:Journal of clinical medicine
影响因子:3.9
作者:
通讯作者:
DOI:10.1016/j.xcrm.2022.100883
发表时间:2023-01-17
期刊:CELL REPORTS MEDICINE
影响因子:14.3
作者:Wu, Junlong;Jin, Shengming;Gu, Chengyuan;Wei, Yu;Zhu, Yao;Necchi, Andrea;Shariat, Shahrokh F.;Pan, Jian;Gan, Hualei;Dai, Bo;Zhang, Hailiang;Shi, Guohai;Zhu, Yu;Shen, Yijun;Zhu, Yiping;Ye, Dingwei
通讯作者:Ye, Dingwei
DOI:10.1016/j.eururo.2020.04.026
发表时间:2020
期刊:European Urology
影响因子:--
作者:Hongkai Wang;Junlong Wu;Yu Wei;Yao Zhu;Dingwei Ye
通讯作者:Dingwei Ye
GLUT1 is an AR target contributing to tumor growth and glycolysis in castration-resistant and enzalutamide-resistant prostate cancers
GLUT1 是一种 AR 靶点,有助于去势抵抗性和恩杂鲁胺抵抗性前列腺癌中的肿瘤生长和糖酵解
DOI:10.1016/j.canlet.2020.05.007
发表时间:2020-08-10
期刊:CANCER LETTERS
影响因子:9.7
作者:Wang, Jun;Xu, Wenhao;Ye, Dingwei
通讯作者:Ye, Dingwei
DOI:10.1158/1078-0432.ccr-20-0587
发表时间:2020-09-01
期刊:CLINICAL CANCER RESEARCH
影响因子:11.5
作者:Wang, Beihe;Liu, Chang;Zhu, Yao
通讯作者:Zhu, Yao
KMT2D突变/缺失调控CMTM4表达促进有氧糖酵解导致前列腺癌PARPi耐药的机制研究
  • 批准号:
    --
  • 项目类别:
    面上项目
  • 资助金额:
    55万元
  • 批准年份:
    2021
  • 负责人:
    朱耀
  • 依托单位:
肿瘤周围脂肪组织调节肾癌生物学行为的机制研究
  • 批准号:
    81370073
  • 项目类别:
    面上项目
  • 资助金额:
    62.0万元
  • 批准年份:
    2013
  • 负责人:
    朱耀
  • 依托单位:
组蛋白甲基转移酶SETD2对肾癌细胞的影响及分子机制研究
  • 批准号:
    81001131
  • 项目类别:
    青年科学基金项目
  • 资助金额:
    18.0万元
  • 批准年份:
    2010
  • 负责人:
    朱耀
  • 依托单位:
国内基金
海外基金