Sox30调控桥粒关键基因抑制肿瘤转移的作用及分子机制研究

Sox30 is a new tumor suppressor gene, which induce tumor cell apoptosis by regulating p53 signaling pathway. Recently, we found Sox30 played an important role in tumor metastasis and this function may be related to the regulation of desmosome-related genes. However, the role and mechanism of Sox30 in tumor metastasis and how to regulate the expression of desmosome-related genes is still unknown. This study is to use Sox30 knockout mouse to further analyze its role in chemical-induced lung cancer and in Sox30 differentially-expressed cell lines. We will also analyze the expression of the desmosome-related genes, the structure of desmosomes in tissues at different stage of chemical-induced lung cancer in knockout mouse. The EMSA, ChIP and Luciferase reporter assay will be used to explore the molecular mechanism of Sox30-regulating desmosomal genes. The DNA binding domain of SOX30 binding to the promoter of desmosomal genes will be analyzed by site-directed mutagenesis. The expression of Sox30 and desmosomal genes, the structure of desmosomes will be detected in tissues from patients with lung cancer. Statistical analysis of the relationship between Sox30 and clinical characteristics, including metastasis and survival, and the relationship between expression of desmosomal proteins and clinical characteristics will be performed. This study will provide a better understanding of the role of Sox30 gene as a tumor suppressor, and provide detailed information for the regulation of desmosomal genes by Sox30.

Sox30基因是我们发现的新的抑癌基因，可激活p53信号通路诱导肿瘤细胞凋亡，但其在生命活动与疾病中的其他功能和机制远不清楚。我们最近发现Sox30在转移肺癌中低(不)表达并与肺癌患者生存时间缩短相关；初步解析Sox30可调控桥粒相关基因抑制转移。推测Sox30参与肿瘤转移是其新的功能，而“Sox30-桥粒基因-桥粒”是其抑制转移的新机制之一。为此，拟通过基因敲除动物化学致癌模型，系统评价Sox30在肿瘤转移中的作用；分析在化学致癌和肺癌转移过程中，Sox30对桥粒基因表达、桥粒结构功能的调控作用及机制；解析“Sox30-桥粒蛋白-下游分子”通路并分析该通路与肺癌临床特征、预后的关系及意义。该研究将揭示Sox30新的抑癌作用和分子机制，丰富对Sox30蛋白质功能和桥粒调控机理的认识，为后续更深入解析Sox30基因的生物学功能、以及用于临床诊断或治疗候选靶标的筛选提供新的资料。

Sox30基因是肺癌发生过程中一个新的抑癌基因，我们最近发现Sox30可调控桥粒相关基因抑制肿瘤转移，推测Sox30参与肿瘤转移是其新的功能，但相关的作用和机制还不清楚。本项目进一步系统评价Sox30在肿瘤转移中的作用；分析在化学致癌和肺癌转移过程中，Sox30对桥粒基因表达、调控作用及机制；解析“Sox30-桥粒蛋白-下游分子”通路并分析该通路与肺癌临床特征、预后的关系及意义。结果发现在肺腺癌中桥粒相关基因表达受Sox30调控，而在肺鳞癌中则没有调控作用；Sox30可直接结合桥粒相关基因基因启动子区ACAAT 序列调控这些基因的转录；体内外的实验研究表明，干扰相关桥粒基因的表达可显著影响Sox30基因对肿瘤生长和转移的调控作用；Sox30基因主要通过桥粒相关基因并影响下游的ERK和Wnt信号通路相关分子发挥抑制作用。此外，我们分析发现Sox30基因调控的桥粒重要基因PKP2可通过影响EGFR通路在肺癌中发挥癌基因的作用。我们的研究进一步证实了Sox30基因的抑癌作用和分子机制，丰富对Sox30蛋白质功能和桥粒调控机理的认识，为后续临床肺癌诊断、治疗候选靶标的筛选提供新的资料。