大鼠和人乳腺癌易感基因RGD1560402的鉴定及功能特征研究

Breast cancer is the most cause of women death in Western world. Using the rat model of MNU-induced mammary carcinoma, we have identified a novel breast cancer susceptibility gene, designated RGD1560402 (RGD). The expression of this gene is downregulated in rat strains that are resistant to MNU-induced mammary carcinoma development. Over-expression of RGD in breast cancer cell lines reduced the rate of tumor proliferation and resulted in anchorage independence growth in vitro. We have identified a human processed gene on chromosome 19 that is similar to the rat RGD gene. It remains to determine whether the rat and human genes have similar functions in breast cancer progression. The overall objective of this application is to determine the functional mechanism of RGD in breast cancer progression. Toward this goal, we plan to study whether over-expression of RGD in breast cancer cell lines can induce glycolytic activity, similar to oncogene PGK-1. We then generate retroviruses overexpressing RGD and inject them into a rat strain and knockout RGD gene that are resistance to MNU-induced breast cancer. We expect enforced RGD expression in these rats overcomes resistance to breast cancer development. Finally, we will examine the relationship between human and rat RGD by examining its expression and function in various human breast cancer cell lines and tumors from patients. This work is expected to lay foundation for further study of the RGD gene as a target for the treatment of breast cancer.

乳腺癌是西方国家妇女死亡的最主要原因。前期使用MNU诱导的大鼠乳腺癌模型研究发现一个新的腺癌易感基因RGD1560402(RGD)。该基因在大鼠中下调表达可抵抗MNU诱导的乳腺癌发生，在乳腺癌细胞中超表达可加速癌细胞增殖而导致在体外的锚定非依赖性生长。在人19号染色体上有一个相似基因，但不确定其功能。为了弄清RGD基因在乳腺癌发生中的功能机制，本课题研究RGD表达对大鼠和人乳腺癌细胞锚定非依赖性生长、糖酵解活性及相关基因表达的影响，阐明RGD基因对乳腺癌细胞生长调控的分子机制；在体内研究RGD基因表达或敲出对乳腺癌发生的影响，确定其作用的靶基因，验证RGD基因是否是bcr/s基因并解析其作用的分子机制；在体内外研究hRGD基因与乳腺癌发生的关联性，弄清人与大鼠RGD基因的功能差异及其调控的靶基因，解析hRGD基因在人乳腺癌发生中的功能机制，为进一步研究RGD基因作为治疗乳腺癌靶标奠定基础。

乳腺癌是西方国家妇女死亡的最主要原因，而遗传因素在乳腺癌的发病机理扮演着重要的角色。我们通过构建了甲基亚硝基脲（MNU）诱导乳腺癌大鼠模型证明了IL24是乳腺癌发生的抑制基因（bcr）。在转基因鼠模型中，IL-24显著地抑制乳腺癌的发展。我们还首次报道了PERP及COTL1作为两个重要的肿瘤抑制基因是通过介导IL-24发挥作用的。RGD1560402基因与磷酸甘油酸激酶1（PGK1）具有91.6%同源性，仅比PGK1少12个氨基酸。在Ha-ras原癌基因诱导的乳腺癌细胞系中，过表达PGK1或者 RGD1560402后有效地增加其在体外或体内的增殖速度。研究发现这2个基因在乳腺癌细胞系中直接受到Ha-RAS基因的调节，且 PGK1也受到TWIST1的调节，而TWIST1则受RAS及转录相关基因ETV1的调节。以上研究揭示了IL-24及RGD1560402与人类乳腺癌的发生有密切联系。基于此，我们发现了一种在体内外有抑制乳腺癌活性的新型的化合物——racemosin B的衍生物。这种衍生物通过抑制自噬起作用，对人类的乳腺癌具有潜在的治疗作用。目前已在《Nature》子刊《Oncogene》等杂志发表高水平论文11篇，其中SCI收录9篇，提交专利2项。