环状RNA circ-FOXO3在三阴性乳腺癌侵袭转移中的作用及机制研究

三阴性乳腺癌（TNBC）具有高度的侵袭性、且缺乏有效的治疗靶点及治疗手段，预后极差。环状RNA（circRNA）是新近发现的一类具有闭合环状结构的非编码RNA，具有重要的基因表达调控功能，与肿瘤的发生发展有密切关联。我们前期采用高通量circRNA芯片分析发现circ-FOXO3在TNBC显著下调表达，且过表达circ-FOXO能抑制TNBC侵袭转移。据此，本项目拟在前期工作的基础上，从分子、细胞、裸鼠以及临床标本水平，进一步明确circ-FOXO3抑制TNBC侵袭转移的的作用；揭示circ-FOXO3抑制TNBC侵袭转移作用中的关键分子事件，解析circ-FOXO3抑制上皮-间质转化、代谢重编程的作用及机制；阐明circ-FOXO3在TNBC下调表达的分子机制；探究circ-FOXO3在TNBC转移中的病理意义，为以circ-FOXO3作为TNBC治疗靶点提供实验基础和理论依据。

Triple-negative breast cancer (TNBC) displayed a highly invasive phenotype, and lack of therapeutic targets for effective treatment, and have a relatively poor outcome. Circular RNAs (circRNAs) are a novel class of non-coding RNA characterized by the presence of a covalent bond linking the 3’ and 5’ ends. Recently studies suggested that circRNA is associated with cancer development by regulating gene expression. In our previous studies, we examined the differential expression profile of circRNAs between TNBC tissues and adjacent non-cancerous tissues with microarray, and found that circ-FOXO3 was markedly down-regulated in TNBC tissues, whereas overexpression of circ-FOXO3 significantly suppressed TNBC cell invasion and metastasis. Therefore, our present proposal will verify the inhibition effects of circ-FOXO3 on TNBC cell invasion and metastasis, investigate pivotal molecular event of circ-FOXO3-mediated inhibition of TNBC cell invasion and metastasis, clarify the role and mechanism of circ-FOXO3 on epithelial-mesenchymal transformation and metabolic reprogramming, clarify the molecular mechanism of down-regulation of circ-FOXO3 in TNBC, and explore the pathological significance of circ-FOXO3 in TNBC cancer metastasis. The results will provide experimental and theoretical basis for circ-FOXO3 serving as therapeutic target for TNBC.