miR-343在乳腺癌细胞转移的EMT及MET过程中的双面功能及机制研究

microRNA (miRNA) has been one of the most intensively studied non-coding RNA. One of the key questions in the field is how miRNAs achieve their funcational specificity due to the redundancy of miRNAs and their targets. Our recent study of let-7 family miRNA has shed a ligh on how similar miRNA can exert the specific functionality in breast cancer. In this study, we have utilized an vivo selection model and miRNA array for screening of those miRNA involved in the MET process of breast cancer. Interestingly, miR-343 was identified for its dual functionality to promote EMT in non-invasive breast cancer cells and MET in highly invasive breast cancer cells. The preliminary mechanistic studies suggest miR-343 could target differential set of oncogenes and tumor suppressor genes in different types of breast cancer cells. We hypothesize that miR-343 might exert its functional specificity depending on the spatial and temporal interaction with differential interactors during the progress of cancer invasion and metastasis. Further in-depth studies will be performed to investigate the functional roles and mechanism of miR-343 in breast cancer invasion and metastasis.

microRNA的研究是非编码RNA研究中最为热门的领域。长期以来有关miRNA功能特异性的关键科学问题一直困扰此领域：种子区序列相近或相同的miRNA群如何实现功能的特异性？特定miRNA所作用的众多靶基因如何特异地整合与传递上游的信号？就前者，我们最近针对let-7家族的功能特异性开展了一些有益的探索。就后者，我们通过筛选调控乳腺癌细胞间质样上皮转化（MET)相关miRNA,发现miR-343在不同的乳腺癌细胞中起着双面的作用，如既可促进上皮间质转化（EMT）又可促进间质上皮转化（MET）。进一步的研究显示，miR-343在不同的乳腺癌细胞系中可以差异性地调控靶基因群（如癌基因与抑癌基因）从而选择性地调控相关的细胞生物学行为。本课题中我们将深入研究miR-343等miRNA在影响肿瘤转移的时空转换过程中呈现的功能特异性及其分子机制，并就所提出的"跷跷板"假说作细致深入的研究。

受本项目资金的支持，项目执行的过去四年按照既定目标就miRNA调控乳腺癌细胞的转移与增殖的分子网络方面开展了系统深入的研究，取得了一系列的研究成果，超额完成了既定的目标与任务。主要代表性的工作包括发现miR-340, miR-26，miR-96-183-183等miRNA可以调控乳腺癌细胞上皮间充质转变以及侵袭及雌激素诱导的乳腺癌细胞增殖；发现CCAR1 5'UTR 作为miR-1254天然增强子抑制乳腺癌干性和恢复乳腺癌细胞的内分泌治疗的敏感性。除此之外还发现纳米物质Gd@C82(OH)22作为新型乳腺癌干细胞靶向药物，并且系统性地研究了包括GH,PRL,ARTN, TFF3等乳腺癌相关的细胞因子，取得了一系列的科研成果。受本基金支持，我们共在Nature Communications、Cell Research、Cancer Research、Small、Cancer Letters、Journal of Biological Chemistry等国际著名期刊发表SCI学术论文13篇，其中IF>10的2篇，10>IF>5的4篇。本项目的圆满完成为进一步深入肿瘤相关非编码RNA方面的研究奠定了良好的基础。