RANKL/RANK通路维持乳腺癌干细胞自我更新作用的研究

Growing evidence suggests that cancer stem cells (CSCs) most likely contribute to tumorigenesis, metastasis and therapy failure.The oncogenic capacity of CSCs is in part due to their ability to self-renew. Although the importance of RANKL/RANK signal pathway for mammary gland development has been clearly demonstrated, it is unknown whether RANKL/RANK plays a role in breast cancer stem cells (BCSCs). We have previous confirmed that RANKL/RANK pathway could promote the migration of breast cancer cells, and found the over-expression of RANK in BCSCs, so the purpose of this study is to explore the role and mechanism of RANKL/RANK in regulating self-renewal of BCSCs.This study will find that the expression of RANK is associated with the marker gene of CSCs self-renewal（Bmi-1）in primary breast cancer specimens.After lentivirus-mediated upregulation or knockdown of RANK expression，we will investigate the change of ability for BCSCs self-renewal in vivo and vitro，and we willl find the Src/STAT3 signal transduction involves in this process. Finally，the study will find that STAT3 can bind to Bmi-1 promoter and activate its transcription, then we will try to explain the moleculor mechanism of RANKL/RANK pathway in self-renewal of BCSCs. These findings may contribute to deepen the understanding of biological characteristic of BCSCs and lead to the development of more effective therapies.

大量研究表明肿瘤干细胞的存在是肿瘤发生、转移及治疗失败的主要原因。维持自我更新能力是肿瘤干细胞存在的关键，但其机制仍未阐明。RANKL/RANK通路在正常乳腺的发育过程中作用重要，但对乳腺癌干细胞的作用与机制尚不明确。我们前期研究证实RANKL/RANK影响乳腺癌细胞迁移能力，RANK在乳腺癌干细胞中高表达，本课题拟进一步探讨RANKL/RANK对乳腺癌干细胞自我更新能力的影响及机制。本项目在临床组织标本中验证RANK与干细胞自我更新标记基因Bmi-1表达相关；通过体内、外实验，观察上调或干扰RANK表达后乳腺癌干细胞自我更新能力的变化，证实Src/STAT3通路介导这一过程；最后阐明下游信号分子STAT3可与Bmi-1启动子结合促进其转录表达，揭示RANKL/RANK影响干细胞自我更新能力分子机制。本研究有助于加深对乳腺癌干细胞生物学特性的认识，为乳腺癌治疗新靶点的选择提供实验依据。

大量研究表明肿瘤干细胞的存在是肿瘤发生、转移及治疗失败的主要原因。维持自我更新能力是肿瘤干细胞存在的关键，但其机制仍未阐明。RANKL/RANK 通路在正常乳腺的发育过程中作用重要，但对乳腺癌干细胞的作用与机制尚不明确。本课题进一步探讨RANKL/RANK 对乳腺癌干细胞自我更新能力的影响及机制。本项目在临床组织标本中验证RANK 与干细胞自我更新标记基因Bmi-1 表达相关，其表达提示预后不佳；通过体内、外实验，观察上调表达或使用重组人RANKL作用后乳腺癌干细胞自我更新能力的变化，证实Src/STAT3 通路介导这一过程，揭示RANKL/RANK 影响干细胞自我更新能力分子机制。本研究有助于加深对乳腺癌干细胞生物学特性的认识，为乳腺癌治疗新靶点的选择提供实验依据。