竞争性内源RNA分子网络调控乳腺肿瘤细胞恶性表型及治疗耐受的研究

The ceRNAs (competing endogenous RNAs）hypothesis revealed a novel type of RNA-RNA interacting model via competitive binding to miRNA pools.This field is still at its infant stage.During the systematic screening of breast cancer associated miRNAs, we have found the loss of miR-1254-1 gene in 10q21.3 of human breast cancer tissue and subsequentially reduced expression of miR-1254.Reduced expression of miR-1254 resulted in multiple pro-oncogneic features by its direct binding to the 3'UTR of 5 target genes (such as EGFR and HER2) and the 5'UTR of its host gene CCAR1.Preliminary data suggests that ceRNAs regulate the expression of each other via miR-1254 and thereby potentially modulate the self-renewal of cancer stem cell and tamxoifen resistance of ER+ breast cancer cells. We will further investigate the mechanism of miR-1254 mediated ceRNA in the regulation of breast cancer development. As multiple miRNAs exerted pronounced specificity, we will also investigate the possible spatial and temporal specificity of the molecular network of ceRNAs and miRNAs under disease-specific context.

竞争性内源RNA（ceRNAs）假说揭示了一种RNA-RNA间由miRNA所介导的崭新的基因表达调控方式,相关研究总体上尚处于萌芽阶段。本课题前期通过系统性筛选乳腺癌相关miRNA,发现miR-1254-1基因在肿瘤组织基因组中发生高频的缺失及表达明显下调,并由此作用于多个靶基因（如EGFR及HER2)的3'UTR以及宿主基因CCAR1 的5'UTR共同促进肿瘤的恶性表型。进一步的研究提示，miR-1254介导的靶标群在调控肿瘤干细胞的自我更新及他莫昔芬治疗耐药过程中借助ceRNA分子网络实现功能与机制的协同。鉴于miRNA的表达及功能往往体现为明显的时空特异性，我们在深入研究miR-1254介导的ceRNA调控乳腺癌细胞恶性表型的分子机制的同时，还就ceRNAs与miRNA表达与互动的辩证过程中可能存在的时空特异性及疾病特异性机制开展有益的探索。

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竞争性内源RNA分子网络调控乳腺肿瘤细胞恶性表型及治疗耐受方面开展了系统的研究，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CCAR1 5'UTR 作为miR-1254天然增强子作用于竞争性内源RNA分子网络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;发现miR-96-183-183, miR-26, miR-135a,miR-191/425等miRNA可以调控乳腺癌细胞的恶性表型及内分泌治疗与化疗耐药。同时还发现纳米物质Gd@C82(OH)22作为新型乳腺癌干细胞靶向药物，并且进一步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、JBC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。