ZIC2作为乳腺癌候选抑癌基因的作用及机制

乳腺癌作为女性发病率最高的恶性肿瘤，是一个分子水平异质性很高的疾病。转录因子作为基因表达调控的上游，在乳腺癌的发生发展过程中起重要的作用。锌指蛋白ZIC2是神经系统的发育过程中重要转录因子。ZIC2在口腔鳞癌、卵巢癌、子宫颈癌和脑膜瘤等肿瘤均表达上调，并与预后不良呈正相关。乳腺癌发生发展中是否存在ZIC2表达异常？及其可能的作用和机制如何？我们的前期研究发现ZIC2在乳腺癌中低表达，且ZIC2的低表达与乳腺癌患者的不良预后相关。体外和体内实验均显示过表达ZIC2可以抑制肿瘤细胞增殖能力和成瘤能力。初步机制研究发现ZIC2可以在启动子活性、mRNA以及蛋白水平上显著下调Bmi1表达。本项目继续探讨已鉴定的潜在靶基因，并拟通过ChIP-seq、表达谱芯片、免疫沉淀和质谱分析等方法深入探讨ZIC2抑制乳腺癌发生发展的机制，为诠释乳腺癌发生发展的分子机制和寻找乳腺癌的治疗新手段提供科学依据。

Breast cancer has the highest incidence of malignant tumors in women and is a molecularly heterogeneous disease. Transcription factor(s) serving as the upstream of gene expression regulation, play an important role in the tumorigensis of breast cancer. ZIC2, one of the members of ZIC family proteins, shares a C2H2 type zinc finger structure and plays an important role during the development of the nervous system. Recently, ZIC2 have been shown to be up-regulated in a variety of tumors including oral squamous cell carcinoma, ovarian cancer, cervical cancer and meningioma, and be positively related with poor prognosis in these cancer patients. Whether the expression of ZIC2 is disregulated, and whether it is involve in the breast cancer development and metastasis are still remain elusive. Our preliminary results showed that ZIC2 is lowly expressed in breast cancer compared to paracancerous tissues, and the low expression of ZIC2 is correlated with the worse outcome of breast cancer patients. In vitro and in vivo studies found that the overexpression of ZIC2 can inhibit tumor proliferation and tumorigenisis capacity. ZIC2 can negatively regulate Bmi1 at promoter activity, mRNA and protein levels. In this project, in addition to investigate the potential target gene identified by Luciferase assay, we will further investigate the alternative mechanisms of how ZIC2 is involved in breast cancer through ChIP-seq, microarray, immunoprecipitation and mass spectrum analysis method etc., providing new insight into ZIC2 as a potential tumor suppressor in breast cancer, revealing molecular mechanisms and new treatment strategies for breast cancer.