ERα-piR-000823-RECK轴调控乳腺肿瘤干细胞机制研究及磁性纳米微粒介导的靶向治疗

piRNA是生殖干细胞特异的一类新型非编码RNA。近期研究表明其在肿瘤及肿瘤干细胞有表达，但功能及机制未明。前期筛选发现piR-000823在管腔型乳腺癌和乳腺肿瘤干细胞异常高表达，敲低piR-000823可降低乳腺肿瘤干细胞比例、抑制干性表征及克隆成球能力，同时上调靶基因RECK；RECK负调控NOTCH信号通路抑制肿瘤细胞干性。ERα转录调控piR-000823，敲低ERα可抑制piR-000823表达。据此提出：ERα-piR-000823抑制RECK激活Notch信号通路，增强乳腺肿瘤细胞干性，促进乳腺癌发展。本项目拟通过体外细胞实验、体内荷瘤动物模型及临床样本分析，揭示piR-000823调控乳腺肿瘤干细胞的功能和机制；探索磁性纳米颗粒递送anti-piR-000823至乳腺肿瘤荷瘤小鼠，验证其抑癌效果。本研究将有助于阐明乳腺肿瘤干细胞的调控机制，为乳腺癌生物学治疗提供新靶点。

piRNA is a new class of non-coding RNA with specific expression in the germ stem cells. Emerging evidence indicates the expression of piRNA in both tumor tissues and tumor stem cells. However, its function and regulatory mechanism remain unclear. Our preliminary data has identified that piR-000823 is highly expressed in ALDH-positive breast cancer stem cells and luminal breast cancer based on the piRNA expression screening, and the regulatory mechanism of piR-000823 on breast cancer stem cells has not been reported yet. Knocking down piR-000823 has reduced the proportion of breast cancer stem cells, and inhibits dry characterization and cloning ability. RECK gene has been identified as a key potential target gene of piR-823 in human breast cancer by our preliminary data and knocking down piR-000823 has reduced the expression of RECK. It has been reported that RECK inhibits CSCs by negatively regulating NOTCH signal pathway. Further research has demonstrated the expression of piR-000823 is promoted by ERα at the transcriptional level. Based on these findings, we hypothesize that piR-000823, activated by ERα, specifically suppress RECK to promote Notch signaling pathway in control of breast cancer stem cells. In this project, breast cancer cell lines, breast-tumor-burden mice and breast cancer clinical samples will be applied to validate the hypothesis. In addition, magnetic nanoparticles will be applied to delivery anti-piR-823 to the breast tumor-burden mice, determining its target-delivery efficiency and cancer-inhibition function. This study will lead to our better understanding of the mechanisms regulating breast cancer stem cells, and provide a new therapeutic target in suppression of breast cancer.