申请人前期工作及近期文献均证明，部分肿瘤细胞分泌的微泡(MV)能够将健康同源细胞驯化成肿瘤，被称为癌症细胞的“传染性”。截至目前，细胞外信号如何影响MV致瘤能力尚未可知，无法提供便捷、高效的调控手段。我们发现TNF-α信号极有可能串联MV的释放及其内容物组装；因此本课题拟探讨TNF-α信号对MV致瘤能力的影响及其分子机制。我们拟首先研究TNF-α信号对白血病MV miRNA表达谱等生物学特性的影响；同时证明TNF-α通过诱导MV中miRNA表达谱改变影响其致瘤能力，在此基础上，初步探讨TNF-α信号影响MV中miRNA分子组装的机制。本课题的完成，有望首次提出TNF-α等细胞外信号通路对MV致瘤能力的影响及机制，TNF-α有望成为干预MV致瘤性的重要调控靶点；同时，初步阐明了MV内容物组装的分子机制及其干预途径，为后期调控MV内容物的研究提供了重要的方法学选择和关键的研究切入点。

Microvesicles (MV), also termed as microparticles, have been described as a novel and important mechanism of intercellular signal communication via fusing with the plasma membrane of the target cell and discharging their cargo into the cytosol. By facilitating the horizontal transfer of bioactive molecules such as proteins, RNAs and microRNAs, MVs are now thought to have vital roles in tumor invasion and metastases, inflammation, coagulation and stem-cell renewal. We have demonstrated that BCR-ABL1–positive MVs could initiate malignant transformation of normal cells (Leukemia, 2014, 28(8):1666-75). Similar work with breast cancer derived MVs, was performed by Melo et al (Cancer Cell, 2014 Nov 10;26(5):707-21) eight months later. Both our papers demonstrated that miRNAs were key key regulatory molecules of tumorigenesis induced by MV. No definite conclusion has been given yet on the tumorigenesis induced by MV about extracellular signals. A few papers have showed that TNF-alpha(α) could alter miRNA-mediated communication by endothelial MVs. Besides, our previous bioinformatics have confirmed that TNF-α might also have an impact on the release of MVs. The aim of this subject is to investigate whether TNF-α could influence the transformation ablility of MVs via altering the miRNA profiles in MV..In this subject, we will figure out the effects of TNF-α signal on MV releasing from leukemia cells. More importantly, we will prove that the transformation ability of MV could be altered via altering the miRNA profiles in MV when TNF-α pathway was blocked or enchanced. Besides, this subject would explore the molecular mechanisms for loading miRNA into MVs. Findings of this subject will sheed much-needed light on the effect of extracellular signal (such as TNF-α) driving malignant reprogramming induced by MV. Furthermore, TNF-α itself could act as an warning indicator and a novel target to regulate the transformation ability of MVs. It also presented a unique opportunity to prospectively study the mechanisms undergone by TNF-α, loading their miRNAs into MV, serving as a convenient and operable model for investigating MVs.