Zic2调控Runx2促进肾癌细胞增殖和血管生成的分子机制

明确肾透明细胞癌发生发展的分子机制对肾癌的诊断和治疗至关重要。我们前期观察到转录因子Zic2在肾癌细胞中高表达，并与肿瘤血管密度及预后差相关。基因芯片结果提示Zic2参与调控Runx2，过表达Zic2促进肾癌细胞增殖和迁移；体外实验显示Zic2与Runx2相互结合；miR-4262可抑制Zic2的表达。因此，我们提出Zic2调控Runx2促进肾癌细胞增殖和血管生成的假说。本项目拟采用一系列分子细胞生物学技术及多种细胞和动物模型，在蛋白表达调控及细胞功能上，明确Zic2和Runx2在肾癌中的表达及其临床意义，揭示Zic2调控Runx2的分子机制，探明miR-4262对Zic2的调控作用，阐述miR-4262-Zic2-Runx2通路在肾癌细胞增殖和血管生成中的作用及其机制，并探讨Zic2在肾癌化疗中的潜在应用价值，为诠释肾透明细胞癌发生发展的分子机制和寻找肾癌治疗新靶点提供充分的科学依据。

Disclosing the molecular mechanism of the initiation and progress of clear cell renal cell carcinoma (CCRCC) is of essential importance for clinical diagnosis and treatment. Lately, we found that the transcriptional factor Zic2 was over-expressed in CCRCC. Increase of Zic2 was significantly associated with mircovessel density (MVD) and unfavorable prognosis. In vitro experiments showed that Zic2 directly bound to Runx2. Gene chip revealed that over-expression of Zic2 induced the expression of Runx2, and subsequently increased the cell proliferation and migration of CCRCC cells. Furthermore, our data demonstrated that miR-4262 could markedly inhibit the expression of Zic2. As a result, we assume that Zic2 interacts with Runx2 to promote cell proliferation and angiogenesis in CCRCC. In this study, we aim to determine the expression of Zic2 and its significance in CCRCC, to disclose the mechanism via which Zic2 regulates Runx2, to reveal the regulation of Zic2 by miR-4262, and to investigate the role of Zic2 in cell proliferation, angiogenesis and chemotherapy in CCRCC, using a series of biological and immunological experiments in cell and animal models. Our study is about to provide evidence that Zic2 is involved in tumorigenesis and development of CCRCC, and suggest Zic2 as a promising therapeutic target in CCRCC.