Osterix在乳腺癌血管生成中的作用及分子机制研究

Osterix（Osx）是成骨细胞分化和骨形成中的关键转录因子。我们前期研究发现Osx在乳腺癌组织和高转移潜能的乳腺癌细胞中显著高表达。通过质谱筛选，我们发现乳腺癌细胞中过表达Osx后，促血管生成因子S100A4蛋白表达水平升高；下调Osx的表达后，S100A4蛋白表达水平随之降低。Real-time PCR和Western blot检测结果进一步证实S100A4表达受Osx的调控。生物信息学分析结果显示S100A4基因的启动子区有5个潜在的Osx结合位点。由此我们推测：Osx通过调控S100A4诱导乳腺癌血管生成，促进乳腺癌的转移。本项目拟通过细胞和动物水平实验以及临床标本检测对此假说进行验证；并运用荧光素酶报告基因实验、凝胶迁移实验等阐明Osx调控S100A4的分子机制。本项目研究结果不仅可以丰富对Osx这一重要转录因子生物学功能的认识，而且可以为临床乳腺癌的预防和治疗提供新的靶点。

Osterix (Osx) is a key transcription factor required for osteoblast differentiation and bone formation. Our previous studies have revealed that Osx was significantly over-expressed in primary breast cancer tissues and metastatic breast cancer cells. Moreover, overexpression of Osx increased the expression of S100A4, an important factor involved in angiogenesis, and down-regulation of Osx led to a decrease in S100A4 protein level in breast cancer cells by mass spectrometric screening. That S100A4 is a downstream gene of Osx was further confirmed by Real-time PCR and Western blot assay. Besides, bioinformatics analyses indicated that there are five potential binding sites of Osx in the promoter of S100A4. Based on our findings and data from the literatures, we postulate that Osx induces angiogenesis, and thus promotes metastasis by regulating S100A4 expression in breast cancer. In this project, we will test this hypothesis using cell lines and mouse models as well as clinical investigations. In addition, the molecular mechanism by which Osx regulates S100A4 will be explored by using dual-luciferase reporter assay, electrophoretic mobility shift assay (EMSA), etc. This project will not only provide new insight into the role of transcription factor Osx, but also suggest its potential as a new target for the clinical intervention in patients with breast cancer.