Twist靶向EphA2促进基底细胞样型乳腺癌转移的机制研究

The poor clinical outcome and prognosis of basal-like breast cancer (BLBC) is mainly attributed to its highly invasive and metastatic nature. Recent researches are focused on the molecular mechanism under its initiation and progression, as well as the identification of new therapeutic targets.Twist is a key transcription factor in BLBC metastasis, which plays an important role in tumorigenesis and development. Previously, we found that EphA2 is also highly expressed in Twist over-expressed T-47D cells. EphA2 could promotes cell proliferation, migration and invasion in BLBC cell line. In vitro assay indicated that the promotion of cell migraton and invasion by Twist may be due to the acceleration of the transcription of EphA2. In this study, we aim to explore the role of Twist in BLBC and clear that the molecular mechanism may be through regulating the transcription of EphA2. We will also elucidate the expression and clinical significance of Twist and EphA2 in BLBC tissues. We propose a new mechanism that Twist inhibits the cell migration, invasion and cancer metastasis of BLBC through regulating the expression of EphA2 gene. Our study may provide evidence and new therapeutic targets for the comprehensive treatment of BLBC.

基底细胞样型乳腺癌（BLBC）因常伴随转移而预后很差，其转移的分子机制及新的治疗靶点是目前研究的热点。Twist作为BLBC转移过程中关键的转录因子，在肿瘤发生与发展中起关键作用。我们的前期研究显示：在Twist过表达的T-47D细胞中，EphA2亦高表达。在MDA-MB-231细胞中敲低EphA2，可抑制其增殖、迁移和侵袭能力。初步的研究表明，Twist可能通过正性调控EphA2，促进BLBC细胞的迁移、侵袭和转移。本项目拟用多个BLBC细胞系采用过表达Twist及沉默EphA2，在细胞水平和动物模型中探讨Twist以及EphA2在BLBC转移中的作用，进一步阐明其分子机制；同时收集BLBC病人的临床标本，探讨Twist/EphA2通路在BLBC的临床预后和治疗方面的意义。这种Twist/EphA2通路调控BLBC转移的新机制，可能为BLBC的综合治疗提供新的依据和靶点。

基底细胞样型乳腺癌（BLBC）是一种独特的乳腺癌亚型,具有很强的侵袭性和转移潜力,且预后不良。因此,了解BLBC转移的分子机制非常重要。Twist1是BLBC转移的关键转录因子,在肿瘤发生发展中起关键作用。在我们的研究中,首次验证了EphA2是BLBC发展中Twist1的下游靶基因。已经表明,异常的EphA2水平参与调节BLBC的发生和发展。BLBC中富含EphA2表达,EphA2功能的丧失抑制了肿瘤生长。与这些发现一致,我们对BLBC数据的分析证明,BLBC中的EphA2大大增加。EphA2表达与BLBC分级、分期和淋巴结转移有关。此外,Twist1与BLBC组织中EphA2表达呈正相关。功能实验表明EphA2沉默抑制了BLBC的增殖、EMT和转移。我们进一步探讨了Twist1和EphA2在BLBC转移中的机制,揭示了Twist1直接靶向EphA2并诱导调节EphA2水平。重要的是,CBX7阻断了Twist1与EphA2的结合,并转录降低了EphA2的表达。值得注意的是,CBX7通过直接靶向启动子来阻止Twist1与EphA2启动子的结合。在这里,我们证明了CBX7在BLBC中表达低，并且与EphA2呈负相关。CBX7通过Twist1 / EphA2轴调节BLBC的增殖和转移。我们还采用异种移植模型研究了CBX7、Twist1和EphA2在体内对BLBC的影响,并提供了CBX7通过Twist1和EphA2抑制BLBC异种移植物肿瘤生长和肺转移的第一个证据。因此，本研究可为BLBC远处转移的诊断和预防提供创新性的治疗靶点。