ZEB1调控LUCAT1转录介导乳腺癌干细胞生物学特征的分子机制

The mechanism underlying breast cancer stem cell (BCSCs) characteristics remains to be fully elucidated. Accumulating evidence implies that long noncoding RNAs (lncRNAs) could play a pivotal role in regulating the characteristics of BCSCs. In our previous study, LUCAT1 related with BCSCs by lncRNA microarray, LUCAT1 related with ZEB1 or SOX2 expression positively. Bioinformatic analysis predicted that LUCAT1 shared the same response elements (MREs) of mir-5582 and act as modulator of miRNA of SOX2. So s hypothesis is proposed that if the LUCAT1 transcription of ZEB1 and LUCAT1 act as miR-5582 "sponges" by sharing common MRE, inhibiting SOX2 miRNA targeting activity on mRNA. If the transcription of LUCAT activated by ZEB1 which participated as competing molecules in the ceRNA network against miR-5582 with the regulation of SOX2 on the stemness of breast cancer. Analyzing the interactions of ZEB1/LUCAT1/miR-5582/SOX2 during the stemness of BCSCs will provideinsights in the mechanisms of pathogenesis in breast cancer which may suggest novel strategies for prognosis, diagnosis and clinical treatment of breast cancer.

介导BCSCs生物学特性的相关机制尚不明确，LncRNA调控BCSCs特性备受关注。课题组通过LncRNA芯片检测到BCSCs中LUCAT1高表达，并与ZEB1及SOX2表达正相关；且预测到LUCAT1存在与ZEB1结合位点及miR-5582以相同的MRE与LUCAT1和SOX2结合。LUCAT1是否被ZEB1激活、进而通过ceRNA机制诱导SOX2调控BCSCs特性呢？有待阐明。本项目拟通过检测交叉干预LUCAT1与miR-5582时BCSCs干性与SOX2表达的相关性，明确LUCAT1以ceRNA机制参与miR-5582调控SOX2介导的BCSCs干性的作用；通过确认ZEB1与LUCAT1启动子关键位点结合调控转录，进一步阐明LUCAT1被ZEB1激活、进而以ceRNA机制诱导SOX2调控BCSCs特性的分子机制。为深入研究BCSCs干性维持机制提供新思路和新靶点。

介导BCSCs生物学特性的相关机制尚不明确，LncRNA调控BCSCs特性备受关注。课题组通过 LncRNA芯片检测到BCSCs中LUCAT1高表达，并与ZEB1及SOX2表达正相关;且预测到LUCAT1存在 与ZEB1结合位点及miR-5582以相同的MRE与LUCAT1和TCF7L2结合。LUCAT1是否被ZEB1激活、进而 通过ceRNA机制诱导TCF7L2调控BCSCs特性呢?有待阐明。本项目拟通过检测交叉干预LUCAT1与mi R-5582时BCSCs干性与TCF7L2表达的相关性，明确LUCAT1以ceRNA机制参与miR-5582调控TCF7L2介导 的BCSCs干性的作用; 通过确认ZEB1与LUCAT1启动子关键位点结合调控转录，进一步阐明LUCAT1被ZEB1激活、进而以ceRNA机制诱导SOX2调控BCSCs特性的分子机制。主要结果有 3. LUCAT1对BCCs干细胞样特性和BCSCs特性的调控；4. LUCAT1与TCF7L2竞争性结合miR-5582-3p调控Wnt/β-catenin信号通路；5. 动物实验验证LUCAT1/miR-5582-3p/TCF7L2轴和Wnt/β-catenin信号通路对乳腺癌干性的调控机制；6. LUCAT1被 被ZEB1激活、进而以ceRNA机制调控。本项目通过分析LUCAT1在乳腺癌组织中的表达情况及其与临床病理因素和预后的相关性，同时旨在阐明LUCAT1调控BCSCs特性的分子机制，有望发现乳腺癌发生发展的新基因表达调控网络，为找到乳腺癌新的诊断标志物和特异性治疗靶点提供理论依据。