tRF-27-ZDXPHO53KSN通过调控Skp2表达促进乳腺癌赫赛汀耐药的分子机制研究

批准号:
81972484
项目类别:
面上项目
资助金额:
55.0 万元
负责人:
殷咏梅
依托单位:
学科分类:
肿瘤治疗抵抗
结题年份:
2023
批准年份:
2019
项目状态:
已结题
项目参与者:
殷咏梅
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中文摘要
赫赛汀耐药是HER2阳性乳腺癌治疗中亟待解决的问题。tRF-27-ZDXPHO53KSN(tRF-27)是在赫赛汀耐药细胞中筛选到的表达上调的一条tRF,具体功能和机制尚不清楚。我们前期结果表明:tRF-27在赫赛汀耐药的细胞和病人肿瘤组织中表达均上调;过表达tRF-27和Skp2均显著降低乳腺癌细胞赫赛汀敏感性,且过表达tRF-27上调了Skp2的mRNA和蛋白水平;RIP实验证实tRF-27能够与KHSRP蛋白结合;KHSRP在Skp2 mRNA 3’UTR上存在潜在结合位点,且敲低KHSRP明显增加Skp2 mRNA的稳定性。由此我们推测:tRF-27通过竞争结合KHSRP提高了Skp2 mRNA稳定性从而上调其表达,进而促进赫赛汀耐药。本项目拟通过细胞、动物和临床研究对此假说进行验证。该项目的研究结果不仅有助于赫赛汀耐药机制的进一步阐明,而且可以为克服乳腺癌赫赛汀耐药提供新的靶点。
英文摘要
Herceptin resistance is a problem to be solved in the treatment of HER2 positive breast cancer urgently. TRF-27-ZDXPHO53KSN (tRF-27) is an up-regulated tRF screened in Herceptin-resistant HER2 positive breast cancer cells. However, Its precise roles and the underlying mechanisms in Herceptin-resistant remain unknown. Our preliminary data showed that tRF-27 was up-regulated in Herceptin-resistant HER2 positive breast cancer cells and tumor tissues from Herceptin-resistant breast cancer patients. Overexpression of tRF-27 and Skp2 caused the decrease of Herceptin sensitivity, respectively. And overexpression of tRF-27 increased the mRNA and protein expression of Skp2 gene. RNA binding protein immunoprecipitation (RIP) assay demonstrated that tRF-27 bound with the RNA binding protein (RBP) KHSRP. Bioinformatics analysis indicated that there were potential binding sites of KHSRP on Skp2 mRNA 3’UTR. mRNA stability assays showed that knockdown of KHSRP increased the mRNA stability of Skp2. Therefore, we proposed the hypothesis that TRF-27 promotes Herceptin resistance by competitive binding with KHSRP, enhancing the stability of Skp2 mRNA, thus up-regulating Skp2 expression. We will test this hypothesis by carrying out cell biological experiments, construction of breast cancer model in nude mice as well as performing clinical investigations. Results of this project will not only contribute to the elucidation of the Herceptin resistance of HER2 positive breast cancer further, but also provide a new target to overcome Herceptin resistance in clinic.
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DOI:10.3390/cancers15030899
发表时间:2023-01-31
期刊:Cancers
影响因子:5.2
作者:
通讯作者:
Risk Signature of Cancer-Associated Fibroblast-Secreted Cytokines Associates With Clinical Outcomes of Breast Cancer.
癌症相关成纤维细胞分泌的细胞因子的风险特征与乳腺癌的临床结果相关
DOI:10.3389/fonc.2021.628677
发表时间:2021
期刊:Frontiers in oncology
影响因子:4.7
作者:Sun C;Wang S;Zhang Y;Yang F;Zeng T;Meng F;Yang M;Yang Y;Hua Y;Fu Z;Li J;Huang X;Wu H;Yin Y;Li W
通讯作者:Li W
DOI:10.1038/s41420-022-00968-9
发表时间:2022-04-12
期刊:CELL DEATH DISCOVERY
影响因子:7
作者:Yan, Xueqi;He, Yaozhou;Yang, Shikun;Zeng, Tianyu;Hua, Yijia;Bao, Shengnan;Yang, Fan;Duan, Ningjun;Sun, Chunxiao;Liang, Yan;Fu, Ziyi;Huang, Xiang;Li, Wei;Yin, Yongmei
通讯作者:Yin, Yongmei
DOI:10.1016/j.isci.2023.108302
发表时间:2023
期刊:iScience
影响因子:5.8
作者:Jie Mei;Ziyi Fu;Yun Cai;Chenghu Song;Jiaofeng Zhou;Yichao Zhu;Wenjun Mao;Junying Xu;Yongmei Yin
通讯作者:Yongmei Yin
DOI:10.1186/s13046-021-01949-z
发表时间:2021-04-27
期刊:Journal of experimental & clinical cancer research : CR
影响因子:--
作者:Yan X;Xie Y;Yang F;Hua Y;Zeng T;Sun C;Yang M;Huang X;Wu H;Fu Z;Li W;Jiao S;Yin Y
通讯作者:Yin Y
诱导“冷肿瘤”转热的新策略:顺铂增强三阴性乳腺癌细胞内PDL1再循环的功能与机制研究
- 批准号:82272667
- 项目类别:面上项目
- 资助金额:52万元
- 批准年份:2022
- 负责人:殷咏梅
- 依托单位:
MDM2在乳腺癌上皮细胞间质转化中的作用及机制研究
- 批准号:81172503
- 项目类别:面上项目
- 资助金额:59.0万元
- 批准年份:2011
- 负责人:殷咏梅
- 依托单位:
肿瘤坏死因子-α对乳腺癌细胞CD44表达的调控以及影响细胞迁徙的机制探讨
- 批准号:30772474
- 项目类别:面上项目
- 资助金额:8.0万元
- 批准年份:2007
- 负责人:殷咏梅
- 依托单位:
国内基金
海外基金
