癌基因miR-21介导PI3K/AKT/mTOR信号通路对乳腺癌细胞生物学特性的影响和机制

OncomiR (oncogenic miRNA) miR-21 is one of the key regulators of breast cancer. In our previous study, we found that miR-21 promoted cell growth, proliferation and migration in breast cancer; miR-21 directly targeted PIK3R1, which was an upstream molecule of mTOR pathway; anti-miR-21 up-regulated PIK3R1 protein and down-regulated AKT, which was the key molecule of PI3K/AKT/mTOR pathway. PIK3R1 is a critical upstream molecular of PI3K/AKT/mTOR signaling pathway. In this study, we will explore the mechanism for miR-21 acting as an oncogene in breast cancer by targeting PIK3R1 and subsequently regulating PI3K/AKT/mTOR pathway. To explore the role of miR-21 inhibitors combined with PI3K/AKT/mTOR inhibitors in tumorgenesis, metastasis and therapeutic implications in breast cancer. This study will help to understand the mechanism for miR-21 in tumorgenesis and progression of breast cancer. More importantly, the translational research will help to develop anti-breast cancer drug with China's independent intellectual property rights.

癌基因miR-21是乳腺癌关键调控分子之一。我们前期研究发现miR-21具有促进乳腺癌细胞生长、增殖和迁移的作用；mTOR通路蛋白PIK3R1是miR-21的靶基因；干扰miR-21可上调PIK3R1蛋白表达，同时下调PI3K/AKT/mTOR信号通路关键分子AKT的表达。本项目以PI3K/AKT/mTOR信号通路关键上游分子PIK3R1为切入点，研究miR-21通过靶向抑制PIK3R1调控PI3K/AKT/mTOR信号通路对乳腺癌体内外生物学行为的影响；研究联合miR-21抑制剂和靶向PI3K/AKT/mTOR药物是否具有协同抑制乳腺癌成瘤、转移和改善预后的作用。本研究将有助于深入理解miR-21在乳腺癌发生/发展中的作用机制，其中的转化性研究将为研发具有我国自主知识产权的抗乳腺癌靶向药物奠定实验基础。

癌基因miR-21是乳腺癌关键调控分子之一。我们前期研究发现miR-21具有促进乳腺癌细胞生长、增殖和迁移的作用；mTOR通路蛋白PIK3R1是miR-21的靶基因。本项目以PI3K/AKT/mTOR信号通路关键上游分子PIK3R1为切入点，明确了miR-21通过靶向抑制PIK3R1表达促进乳腺癌体内、外细胞生长、迁移、侵袭；阐明了miR-21靶向抑制PIK3R1激活PI3K/AKT/mTOR信号通路的分子机制；明确了联合miR-21抑制剂和PI3K抑制剂（LY294002）或mTORC1抑制剂（Rapamycin）具有抑制乳腺癌体内成瘤的作用。明确了PIK3R1蛋白（p85α）地表达与乳腺癌PR阳性相关，并且是乳腺癌的5年总生存和无病进展生存的独立预后因素。本研究超计划发现：在乳腺癌中NFKB通过与miR-21启动子功能区结合调控miR-21的表达。本研究将有助于深入理解miR-21在乳腺癌发生/发展中的作用机制，其中的转化性研究将为研发具有我国自主知识产权的抗乳腺癌靶向药物奠定实验基础,为乳腺癌诊断、预后判断以及治疗靶点的选择提供实验依据。