Polyphyllin Ⅶ靶向moesin抑制多发性骨髓瘤干细胞样细胞的研究

批准号:
81970195
项目类别:
面上项目
资助金额:
55.0 万元
负责人:
萧小鹃
依托单位:
学科分类:
骨髓瘤与浆细胞疾病
结题年份:
2023
批准年份:
2019
项目状态:
已结题
项目参与者:
萧小鹃
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中文摘要
研究表明多发性骨髓瘤干细胞样细胞(MMSC)是MM复发和耐药的主要原因。抑制MMSC是治疗MM新策略。项目组首次发现Polyphyllin Ⅶ(PP7)能明显降低侧群细胞存活率、乙醛脱氢酶水平和抑制关键干性基因,通过调控MMSC发挥抗MM效应。用DARTS技术鉴定得到候选靶标moesin(MSN)蛋白,并通过蛋白质免疫印迹和RNA干扰实验得到验证。且PP7降低MSN蛋白水平,转录组测序分析发现Wnt/β-catenin通路受到抑制。已报道MSN在多种肿瘤中高表达,可和CD44相互作用,与肿瘤干性和多药耐药性相关,但在MM干性研究中未见报道。由此本项目提出科学假说:PP7通过下调MSN,减弱其与CD44的相互作用,抑制Wnt/β-catenin通路,抑制MM细胞的干性及多药耐药性。本项目将建立MSN在MM干性调控的机制和PP7通过MSN抗MM的效应机制,为发现MM治疗的候选药物提供新策略。
英文摘要
Recent studies show that multiple myeloma stem-like cells (MMSCs) are likely the main cause of MM relapse and drug resistance. Inhibition of MMSC becomes a new hot spot of MM therapy. We have first demonstrated that polyphyllin Ⅶ(PP7) treatments resulted in survival rate of the side population,decreased levels of aldehyde dehydrogenase and key stemness genes. This anti-MM effect is mainly exerted through the MMSC pathway. We have also identified the target moesin (MSN) protein using DARTS, and verified it by Western blotting and RNAi . Further, PP7 down-regulated MSN at protein level, and transcriptome sequencing data indicated that Wnt/beta-catenin pathway was inhibited. MSN is broadly enriched in tumors and known to function through binding to CD44 and result in Wnt/β-catenin pathway activation, therefore enhance the cancer stem cells and multidrug resistance in tumor cell lines. However, there is no report in the study of MM stemness. In this study, we hypothesize that PP7 attenuates the interaction between MSN and CD44 by targeting MSN, leading inhibition of the Wnt /β-catenin pathway, thereby inhibits the cancer stem cells. Meanwhile, the down-regulation of MSN inhibits the multidrug resistance of MM. This proposed study will establish the mechanism of MSN regulating MM stemness and the mechanism of anti-MM effect of PP7 through MSN, which will provide a potential new strategy of the discovery of candidate drugs for MM therapy.
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专利列表
DOI:10.1016/j.canlet.2022.216019
发表时间:2022-12-07
期刊:CANCER LETTERS
影响因子:9.7
作者:Li, Zhenzhen;Wang, Haiqin;Xiao, Xiaojuan
通讯作者:Xiao, Xiaojuan
DOI:10.1016/j.biomaterials.2023.122096
发表时间:2023-04-17
期刊:BIOMATERIALS
影响因子:14
作者:Xiao,Xiaojuan;Ma,Zekang;Liu,Jing
通讯作者:Liu,Jing
DOI:10.1016/j.canlet.2021.08.009
发表时间:2021-08-16
期刊:CANCER LETTERS
影响因子:9.7
作者:Yi, Hui;Liang, Long;Xiao, Xiaojuan
通讯作者:Xiao, Xiaojuan
DOI:10.3390/cancers13143523
发表时间:2021-07-14
期刊:Cancers
影响因子:5.2
作者:Guo W;Wang H;Chen P;Shen X;Zhang B;Liu J;Peng H;Xiao X
通讯作者:Xiao X
The Role of CREBBP/EP300 and Its Therapeutic Implications in Hematological Malignancies.
CREBBP/EP300的作用及其在血液恶性肿瘤中的治疗意义。
DOI:10.3390/cancers15041219
发表时间:2023-02-14
期刊:Cancers
影响因子:5.2
作者:
通讯作者:
RNA结合蛋白与多发性骨髓瘤
- 批准号:2025JJ20090
- 项目类别:省市级项目
- 资助金额:0.0万元
- 批准年份:2025
- 负责人:萧小鹃
- 依托单位:
Periplocin 靶向SHMT2 克服多发性骨髓瘤耐药的机制研究
- 批准号:2022JJ30790
- 项目类别:省市级项目
- 资助金额:0.0万元
- 批准年份:2022
- 负责人:萧小鹃
- 依托单位:
石蒜碱抑制HMGB1介导的自噬增强多发性骨髓瘤化疗敏感性的作用机制研究
- 批准号:81600184
- 项目类别:青年科学基金项目
- 资助金额:18.0万元
- 批准年份:2016
- 负责人:萧小鹃
- 依托单位:
国内基金
海外基金
