耐药靶标Transgelin2与PI3K/PTEN/Akt通路反馈作用参与乳腺癌侵袭转移的机制研究

Chemotherapy is an important reason of drug resistance, invasion and metastasis produced in breast cancer. Based on the potential drug-resistant target, it is becoming the popular issue of current research to elucidate its mechanism of resistance, invasion and metastasis in breast cancer and explore its regulatory mechanism in network of the signaling pathway. In previous study, we successfully established the paclitaxel-resistant human breast cancer cell line and found Transgelin 2 is the molecular target of the drug-resistant breast cancer, which overexpression could inhibit PTEN level by activating PI3K/Akt pathway, and inactivation of Akt could also suppress the expression of Transgelin 2. Moreover, the resistant cells possessed the strong ability of invasion and metastasis. But the mechanism that Transgelin 2 induces invasion and metastasis has not yet entirely illuminated in breast cancer. This project is in-depth study of previous work, we will investigate the mechanism of drug-resistant target Transgelin 2 inducing invasion and metastasis from in-vitro, in-vivo and clinical specimens. And we will illustrate regulatory mechanism of Transgelin 2 in the signaling pathway using the feedback effect between it and PI3K/PTEN/Akt pathway from transcription, epigenetics and protein levels. The clinical value of Transgelin 2 will be clarified in the auxiliary diagnosis of chemotherapy resistance, invasion and metastasis in breast cancer. These will provide important scientific basis for improving chemotherapeutic effect of breast cancer.

化学治疗是乳腺癌产生耐药及侵袭转移问题的重要原因。以潜在耐药靶标为基础，阐明其在耐药和侵袭转移中的作用机理，探索它在信号网络中的调控机制是目前研究的热点。前期我们已成功建立了人乳腺癌紫杉醇耐药细胞株，并发现Transgelin 2是乳腺癌耐药分子靶标，它过表达可下调PTEN激活PI3K/Akt通路；抑制Akt活性又可降低Transgelin 2表达，此外，该耐药细胞还有较强的侵袭转移能力，但Transgelin 2是否诱导该过程发生并未完全阐明。本项目是既往研究的深入，拟从细胞、裸鼠模型及临床样本三水平探讨Transgelin 2诱导乳腺癌侵袭转移的作用机制；并利用其与PI3K/PTEN/Akt通路的反馈作用，从转录、表观遗传和蛋白水平三方面阐明Transgelin 2在信号网络中的调控机制，明确其在乳腺癌化疗中辅助诊断耐药和侵袭转移的临床应用价值，为提高乳腺癌化疗疗效提供重要的科学依据。

乳腺癌是威胁全球女性健康及生命最常见的恶性肿瘤之一，其发病率及死亡率均处于女性恶性肿瘤前列。紫杉醇（paclitaxel, PTX）是临床治疗乳腺癌的一线药物，但是，随着它不断应用产生的多药耐药问题显著影响其治疗效果。本课题组前期通过低浓度紫杉醇持续诱导法建立了乳腺癌紫杉醇耐药细胞MCF-7/PTX，采用蛋白组学方法筛选得到了潜在的乳腺癌紫杉醇耐药靶标Transgelin-2，即肌动蛋白结合蛋白2，其在耐药细胞MCF-7/PTX中的表达比敏感细胞MCF-7/S中高15.48倍。研究表明肿瘤耐药的发生与侵袭转移存在一定的联系，但耐药靶标Transgelin-2在诱发乳腺癌侵袭转移的分子机制还有待于进一步探索。. 本研究首次证明乳腺癌紫杉醇耐药细胞MCF-7/PTX同时具有较强的侵袭转移能力，且与侵袭转移相关的PI3K/Akt/GSK-3β信号通路在MCF-7/PTX细胞中激活；临床水平上发现，与癌旁及正常组织相比，Transgelin-2在癌组织中显著高表达；生物信息学分析表明，Transgelin-2与临床病理参数和患者预后显着相关，证明Transgelin-2对乳腺癌的诊断具有一定的参考价值；细胞水平证明，Transgelin-2能够促进人乳腺癌侵袭转移；动物水平发现，高表达Transgelin-2增强裸鼠肺转移模型的肺转移结节数。此外，高表达Transgelin-2通过可增加Akt和GSK-3β的磷酸化水平并降低PTEN的表达来激活PI3K/Akt/GSK-3β途径，且Transgelin-2可以直接与PTEN相互作用并位于PTEN的上游。. 作为潜在的乳腺癌治疗靶标，Transgelin-2为开发新的乳腺癌靶向治疗药物及临床乳腺癌的个体化治疗提供了坚实的理论基础和科学依据。