Snail/Ajuba/ERα多蛋白复合体在乳腺癌转移中作用的研究

Breast cancer, with the highest morbidity and mortality, is one of the most common female malignancies in China. Its recurrence and metastasis is suggested to lead the high mortality, but the underlying mechanism remains elusive. Thus, it is crucial to identify :1) the pathway of cancer genesis and metastasis as well as its progression and 2) the biochemical and molecular mechanism of hormonotherapy. Our previews study shows LIM protein Ajuba, coordinating with transcription factor Snail, can suppress the expression of E-cadherin, thereby playing a important role in Snail-induced cancer metastasis; in addition, recent study reveals that Snail, Ajuba and ERα can form a multi-protein complex. Based on the above evidence, we raised the following hypothesis: Ajuba, as a linking protein, mediates the interaction between ERα and Snail. Snail/Ajuba/ERα multi-protein complex is an important contributor to cancer genesis and metastasis. Our study upon the mechanism as to how Ajuba mediates the Snail-ERα interaction will provide the basic theoretical support and a potential target to new breast cancer therapy.

乳腺癌是是最常见的女性肿瘤之一，在我国其发病率及致死率一直居于女性恶性肿瘤的首位；乳腺癌的复发及转移导致了其高死亡率，但这方面的机理还不十分清楚，因此，寻找癌发生和转移的途径，阐明转移的发生发展与激素治疗的生化与分子机制，显得尤为重要。我们前期研究表明LIM蛋白Ajuba是转录因子Snail的共抑制因子，抑制E-cadherin的表达，对Snail诱导的肿瘤转移发挥重要作用；最近研究发现Snail、Ajuba和雌激素受体ERα共同组成了一个多蛋白复合体。基于以上研究我们提出了如下假说：Ajuba作为衔接蛋白介导了雌激素受体ERα与Snail因子间的相互作用。Snail/Ajuba/ERα多蛋白复合物在癌发生和促癌转移中发挥了重要作用。为此，我们希望通过本项研究能阐明Ajuba在介导Snail与ERα间相互作用的机制，进而为找到新的更加有效的乳腺癌治疗案提供基础理论支撑和靶点。

乳腺癌是是最常见的女性肿瘤之一，在我国其发病率及致死率一直居于女性恶性肿瘤的首位；乳腺癌的复发及转移导致了其高死亡率，但这方面的机理还不十分清楚，因此，寻找癌发生和转移的途径，阐明转移的发生发展与激素治疗的生化与分子机制，显得尤为重要。通过本项课题的研究，我们①确立了Ajuba是介导Snail和ERα信号交互相作用用的媒介分子：全长序列的Ajuba才能与ERα产生相互作用，且Ajuba能增强ERα下游靶基因的转录活性；②确立了Snail/Ajuba/ERα多蛋白复合体是乳腺癌细胞获得迁移能力的分子基础：过表达Ajuba能诱导内源性ERα靶基因表达，促进乳腺癌细胞的增殖和迁移。通过上述研究，我们阐明了Ajuba在介导Snail与ERα间相互作用的机制，进而为找到新的更加有效的乳腺癌治疗方案提供基础理论支撑和靶点。