Girdin对乳腺癌干细胞特性的调控作用及机制

It was found that Girdin highly expressed in the triple-negative breast cancer, and related to the distant metastasis of breast cancer.Girdin maybe a new potential target in the treatment of triple-negative breast cancer. In the pre-trial, we observed that Girdin+/CD44+/CD24- breast cancer cells got a significantly high tumorigenic capability compared to Girdin-/CD44+/CD24- tumor cells in the MD-231 cell line.Moreover,microarray analysis revealed that the key factors of PI3K-Akt pathway, such as Akt, PI3K and mTOR were signicantly upregulated in Girdin+/CD44 +/CD24- in breast tumor cells compared to the control group.It demonstrated that Girdin + may be through PI3K-Akt signaling pathway to maintain the stemness of breast cancer stem cell, but the specific mechanism need to be studied. The project try to investigate the relationship between Girdin and PI3K-Akt signaling pathway and the stemness of breast cancer stem cells by interventing the Girdin expression through siRNA and plasmidtransfection test. We also detect the changes of tumor stem cell property and the tumorigenicity in order to study the regulation mechanism of Girdin and explore new potential target for breast cancer, especially triple-negative breast cancer.

Girdin在三阴乳腺癌中高表达，且跟乳腺癌的预后密切相关，其极可能是三阴性乳腺癌治疗的新的潜在靶点。前期工作中，申请者发现在细胞系MD-231中Girdin+/CD44+/CD24-乳腺肿瘤细胞较Girdin-/CD44+/CD24-乳腺肿瘤细胞具有更高致瘤性。并且基因芯片分析揭示PI3K-Akt信号传导通路主要因子Akt、PI3K和mTOR在Girdin+/CD44+/CD24-乳腺肿瘤细胞中表达上调。提示Girdin可能通过PI3K-Akt信号传导通路调控乳腺癌干细胞特性，然而目前具体机制不清楚。本项目拟通过siRNA和质粒转染技术经体内外对Girdin的表达进行干预，检测乳腺癌肿瘤干细胞致瘤性及乳腺癌增值的变化，从而为阐明Girdin对乳腺癌干细胞特性的调控作用及机制、探索乳腺癌（尤其是三阴性乳腺癌）的治疗新途径提供理论和实验依据。

Girdin在三阴乳腺癌中高表达，且跟乳腺癌的预后密切相关，其极可能是三阴性乳腺癌治疗的新的潜在靶点。我们发现在细胞系MD-231中Girdin+/CD44+/CD24-乳腺肿瘤细胞较Girdin-/CD44+/CD24-乳腺肿瘤细胞具有更高致瘤性。基因芯片分析揭示PI3K–Akt信号传导通路主要因子Akt、PI3K和mTOR在Girdin+/CD44+/CD24-乳腺肿瘤细胞中表达上调。提示Girdin可能通过PI3K–Akt信号传导通路调控乳腺癌干细胞特性。我们发现乳腺癌组织中Girdin表达与PI3K表达正相关，单因素分析发现二者共表达乳腺癌远处转移相关，多因素分析发现二者共表达与乳腺癌淋巴结转移、远处转移及组织学类型相关。通过siRNA和质粒转染技术经体内外对Girdin的表达进行干预，检测PI3K–Akt信号传导通路相关因子的变化和乳腺癌肿瘤干细胞致瘤性及乳腺癌增值的变化发现Girdin通过PI3K–Akt信号传导通路成为乳腺癌肿瘤干细胞维持干细胞特性的重要因素。