调控三阴乳腺癌干细胞自我更新和干细胞特性维持的分子开关：miR-4319

The existence of cancer stem cells (CSCs) in triple neginative breast cancer (TNBC) accounts for tumour treatment failure. miR-4319 is found through our miRNA chip screening, and has a significantly lower expression in CSCs of TNBC. Our preliminary study found that overexpression of miR-4319 significantly inhibited self-renewal and stemness maintenance of CSCs. Moreover, bioinformatics and experimental results suggest that Musashi1 may be a downstream target for miR-4319. Literature reports and experimental results confirmed that Musashi1 is closely related to the CSCs of TNBC self-renewal and stemness maintenance. Therefore, miR-4319 may affect CSCs self-renewal and stemness maintenance through Musashi1. This project aims to clarify the biological characteristics of miR-4319 in CSCs, assess the effect of miR-4319 on CSCs self-renewal and stemness maintenance through overexpression and silencing strategies, and demonstrate the molecular mechanism behind how miR-4319 influences CSCs self-renewal and stemness maintenance with Musashi1 as a clue. The mechanism of how miR-4319 regulates CSCs function has not been reported in the past, and as a result, this study could potentially find a new target for the effective treatment of TNBC by CSCs.

肿瘤干细胞(CSCs)的存在是三阴乳腺癌（TNBC）治疗失败的关键原因。miR-4319是我们通过miRNA芯片筛选获得的、显著低表达于TNBC CSCs的miRNA 。前期发现miR-4319过表达显著抑制CSCs的自我更新能力及干性维持功能;生物信息学及实验结果初步表明Musashi1可能是miR-4319的下游靶基因;而文献报道及实验结果证实Musashi1与TNBC CSCs的干性特征密切相关。因此,miR-4319可能通过Musashi1影响CSCs的干性。本课题拟:阐明miR-4319在CSCs中的生物学特征;采用过表达和沉默策略,评估miR-4319对CSC干性维持的影响 ;以Musashi1为机制线索,论证miR-4319影响CSCs干性维持的分子机制。miR-4319调控CSCs的机制研究未见报道, 本研究具有源头创新性,可为通过CSCs而有效治疗TNBC提供新靶点。

肿瘤干细胞(CSCs)的存在是三阴乳腺癌（TNBC）治疗失败的关键原因，CSC比例与TNBC预后密切相关。CSC占比高是乳腺癌预后差的关键因素，且与乳腺癌化疗耐药和侵袭转移相关。肿瘤干细胞中miRNA在干细胞自我更新和增殖中发挥着重要的作用，但目前相关研究甚少。我们前期通过高通量测序筛选TNBC和非TNBC的CSC中差异表达的miRNAs，结果显示共有193条miRNAs的表达具有差异。通过将差异表达miRNAs的潜在靶基因进行功能聚类分析和信号通路聚类分析，我们发现miR-4319是显著低表达于TNBC CSCs的miRNA，并且可能参与调控CSC的干性。体外和体内实验结果均提示，miR-4319能够通过E2F2显著抑制TNBC-CSC的自我更新，并且阻断肿瘤发生和侵袭转移。因此，我们推测miR-4319有可能是乳腺癌的预后指标或治疗靶点。