犹素修饰系统关键蛋白UFBP1调控胃癌细胞对铂类化疗药物敏感性的机制研究
结题报告
批准号:
31971353
项目类别:
面上项目
资助金额:
62.0 万元
负责人:
许国强
依托单位:
学科分类:
生命组学技术
结题年份:
2023
批准年份:
2019
项目状态:
已结题
项目参与者:
许国强
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中文摘要
胃癌是全球和我国死亡率最高的肿瘤之一,易对化疗药物产生耐药性,但调控胃癌细胞对化疗药物敏感性的机制还不清楚。我们前期实验发现犹素(UFM1)修饰系统关键蛋白UFBP1高表达显著延长铂类药物化疗胃癌病人无瘤生存期,定量蛋白质组学和生物化学实验发现UFBP1下调转录因子Nrf2蛋白水平及其下游醛酮还原酶超家族基因AKR1Cs的mRNA和蛋白水平,并促进顺铂诱导胃癌细胞凋亡。结合UFBP1介导犹素化修饰和促进蛋白降解、及Nrf2/AKR1Cs高表达导致肿瘤耐药的前期报导,我们推测UFBP1通过促进Nrf2的犹素化和泛素化降解来抑制下游基因表达,从而增强胃癌细胞对铂类化疗药物的敏感性。为证实这一假说,我们拟用定量和修饰蛋白质组学筛选UFBP1介导的犹素化修饰和下调蛋白,通过分子、细胞、小鼠荷瘤等实验阐明其作用的分子机制。本课题将发现增强胃癌细胞药物敏感性的新通路,为胃癌病人个体化治疗提供理论依据。
英文摘要
Gastric cancer is one of the cancers with the highest mortality globally and in China. It is prone to develop drug resistance. However, the molecules that enhance the sensitivity of gastric cancer to chemotherapeutic drugs and the underlying molecular mechanisms are not completely clear. Our preliminary analysis of tumor samples from gastric cancer patients treated with platinum-based chemotherapy showed that the disease free survival rate is significantly increased for patients with high expression of UFBP1 (UFM1-binding and PCI domain-containing protein 1), a key component in the UFM1 (ubiquitin-fold modifier 1) conjugating system. Our quantitative proteomics and biochemical studies discovered that UFBP1 downregulates the protein level of transcription factor Nrf2 and the mRNA and protein level of its downstream genes aldo-keto reductase 1Cs (AKR1Cs), leading to the enhanced apoptosis upon cisplatin treatment. Together with previous discovery that UFBP1 promotes protein ufmylation and ubiquitin-mediated protein degradation and that high expression of Nrf2/AKR1Cs leads to drug resistance of cancer cells, we hypothesize that UFBP1 enhances drug sensitivity of gastric cancer cells to platinum-based chemotherapy through increasing the ufmylation of Nrf2 and its ubiquitin-mediated degradation and thus reducing the expression of downstream genes. To confirm this hypothesis, we will utilize quantitative proteomics and modification-specific proteomics to screen proteins whose expression and ufmylation are modulated by UFBP1. Then, we will use molecular biology techniques (including gene expression, knockdown and CRISPR/Cas9 knockout), gastric cancer cell lines, and xenograft mouse model to elucidate the mechanisms at the molecular level and at the post-translational modification level. We expect that this work will discover new signaling pathway for drug sensitivity to gastric cancer and provide valuable information for personalized treatment of gastric cancer patients.
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DOI:10.1016/j.jprot.2020.103996
发表时间:2020-10
期刊:Journal of proteomics
影响因子:3.3
作者:Zhanhong Hu;Hongcheng Li;Xiaohui Wang;K. Ullah;Guoqiang Xu
通讯作者:Zhanhong Hu;Hongcheng Li;Xiaohui Wang;K. Ullah;Guoqiang Xu
DOI:10.1002/chem.202300414
发表时间:2023-05-10
期刊:CHEMISTRY-A EUROPEAN JOURNAL
影响因子:4.3
作者:Chen,Cong;Lu,Chengpiao;Li,Jia-Bin
通讯作者:Li,Jia-Bin
DOI:10.1021/acs.jproteome.3c00107
发表时间:2023-06
期刊:Journal of proteome research
影响因子:4.4
作者:Xiaohui Wang;Lindong Cao;Honglv Jiang;Liang Zhou;Zhanhong Hu;Guoqiang Xu
通讯作者:Xiaohui Wang;Lindong Cao;Honglv Jiang;Liang Zhou;Zhanhong Hu;Guoqiang Xu
UFBP1, a key component in ufmylation, enhances drug sensitivity by promoting proteasomal degradation of oxidative stress-response transcription factor Nrf2
UFBP1 是 ufmylation 的关键成分,通过促进氧化应激反应转录因子 Nrf2 的蛋白酶体降解来增强药物敏感性
DOI:10.1038/s41388-020-01551-1
发表时间:2020-11-20
期刊:ONCOGENE
影响因子:8
作者:Hu, Zhanhong;Wang, Xiaohui;Xu, Guoqiang
通讯作者:Xu, Guoqiang
DOI:10.1016/j.bbagrm.2023.194958
发表时间:2023
期刊:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
影响因子:--
作者:Honglv Jiang;Xiaohui Wang;Jingjing Ma;Guoqiang Xu
通讯作者:Guoqiang Xu
泛素连接酶底物受体DCAF15介导胃癌细胞凋亡的机制及靶向药物研究
  • 批准号:
    --
  • 项目类别:
    面上项目
  • 资助金额:
    58万元
  • 批准年份:
    2021
  • 负责人:
    许国强
  • 依托单位:
泛素连接酶底物受体cereblon及其突变体调控神经发育机制的研究
  • 批准号:
    31670833
  • 项目类别:
    面上项目
  • 资助金额:
    65.0万元
  • 批准年份:
    2016
  • 负责人:
    许国强
  • 依托单位:
ADAM12的水解功能在小细胞肺癌增殖和转移中的分子机制研究
  • 批准号:
    31470772
  • 项目类别:
    面上项目
  • 资助金额:
    85.0万元
  • 批准年份:
    2014
  • 负责人:
    许国强
  • 依托单位:
来那度胺治疗多发性骨髓瘤的分子机制研究
  • 批准号:
    31270874
  • 项目类别:
    面上项目
  • 资助金额:
    80.0万元
  • 批准年份:
    2012
  • 负责人:
    许国强
  • 依托单位:
国内基金
海外基金