肿瘤转移是一个复杂的过程，取决于肿瘤细胞中转移促进因素和抑制因素之间的平衡。许多细胞内的癌基因，抑癌基因和转移抑制基因在肿瘤演进的过程中都起着重要的调控作用。肿瘤细胞的持续激活STAT3与肿瘤转移密切相关，并且转移组织中的STAT3的活性较原位组织中还要高。推测STAT3活性的增加可能是由于在肿瘤进程中抑制蛋白的功能缺失或表达减少所致。我们前期利用siRNA干扰技术、报告基因双报告实验及染色质免疫沉淀等技术研究表明，转移抑制基因nm23-H1不仅是STAT3的靶基因，而且负调控STAT3的活性。我们还发现转录因子FoxO3抑制nm23-H1表达。本项目拟在上述重要前期发现的基础上进一步深入探索，利用定点突变、基因芯片和体外基因表达调控等技术，系统研究以全面阐明nm23-H1调控STAT3活性的分子机制和FoxO3抑制nm23-H1表达的分子机理，为揭示转移抑制基因作用的机理提供根据。

Lung cancer is the leading cause of cancer-related mortality worldwide. The major cause of death in patients with lung cancer is the development of metastatic disease. The lack of curative treatment may reflect the poorly understood biological processes that drive metastasis.Tumor metastasis is a complex process depending on metastasis promotion and suppression balance in tumor cells. Many alterations of cellular oncogenes, tumor suppressor genes and metastasis suppressor genes are known to have important roles in controlling cancer progression. Metastasis suppressor genes are characterized by their ability to inhibit the development of metastasis. The biochemical mechanism of metastasis suppressor is thought to attenuate the metastasis promotion pathways.Previous studies showed that persisent STAT3 activation is a critical event in cancer progression and metastasis and levels of STAT3 activity in metastatic melanoma were higher than primary melanoma tissues when using human melanoma brain metastasis animal model. We speculated that the increased STAT3 activity might be attributed to a loss-of-function or reduction of expression of inhibitory protein during cancer progression, and nm23-H1, which was first metastasis suppressor gene to be identified on the basis of an inverse relationship between nm23-H1 expression and metastasis stage, might play a role in regulating STAT3 activity. Our Studies now have identified a new function of nm23-H1 as a metastasis suppressor acting through a negatively regulation of STAT3. nm23-H1 knockdown significantly enhanced IL-6-induced STAT3 phosphorylation, and the effect of nm23-H1 depletion on STAT3 activity was reversed by ectopic re-expression of shRNA-resistent nm23-H1 protein. Moreover, active STAT3 directly binds to nm23-H1 promoter and induces nm23-H1 expression. Based on above findings, we will study throughly the mechanism underlying negative regulation of STAT3 by nm23-H1. We will also study the mechanism by which FoxO3 supppressed nm23-H1 expression. We believed this feedback network might provide insight into the function of metastasis suppressor genes and could be a logical new target for the design of the therapeutic strategies for treatment of metastasis diseases.