SOX7在肾细胞癌中的异常甲基化及其功能机制研究

Epigenetics regulation has become the hotspot in the basic and clinic research of renal cell cancer (RCC) , the aberrant methylation of a large number of tumor suppressors has been reported to closely relate to tumorigenesis and development of renal cell cancer . Therefore we should screen out a large number of candidate tumor suppressor genes regulated by epigenetics and explore their function and related mechanism in RCC , which not only contribute to the analysis of the occurrence and development of RCC ,but also the clinical diagnosis and treatment of RCC . Based on the evidence from previous studies ,we have screened out SOX7 , a tumor suppressor gene, which has been down-regulated because of the hypermethylation of promoter .According to our previous results , we found that the expression of SOX7 has greatly decreased or transcriptional silenced in RCC cell lines and tumor tissues ,compared with the normal renal cell and adjacent normal kidney tissues . However , the expression of SOX7 can be reversed by drug-induced demethylation in RCC cell lines .Next, we will continue to verify the function of tumor suppressor gene SOX7 in renal cell carcinoma. In addition , we will analyse the methylation status of SOX7 with 270 paired samples we have collected to verify the relationship between SOX7 methylation and clinical pathological information . At the same time , we suppose to combine methylation chip and expression profile chip analysis to screen out more candidate tumor suppressor genes which was down-regulated or transcriptional silenced by aberrant promoter methylation , in order to enrich renal cell carcinoma specific methylation profiles.

表观遗传学调控是近年来肾癌临床及基础研究的热点问题，已有研究证实某些抑癌基因启动子区异常甲基化与肾癌的发生发展密切相关。因此筛选出肾细胞癌中受表观调控的候选抑癌基因并分析其作用机理，对进一步认识肾癌的发生发展具有重要理论价值，同时对肾癌的临床诊疗也具有重要的指导意义。在前期工作基础中，我们筛选出在肾癌中发生启动子区异常甲基化的候选抑癌基因SOX7，通过预实验，我们发现与正常肾细胞系及癌旁正常肾组织相比，SOX7在肾癌细胞系及肾癌组织中的表达明显下降，且在肾癌细胞系中通过去甲基化药物处理可诱导其重新表达。接下来，我们将继续探索SOX7在肾癌中的抑癌作用及相关机制，并结合本课题组已收集的270例肾癌及癌旁正常肾组织标本，验证其甲基化水平与临床病理信息的相关性。同时拟利用甲基化芯片和表达谱芯片联合分析，筛选更多在肾癌中受甲基化调控而表达减少或沉默的候选抑癌基因，扩充肾癌特异性抑癌基因甲基化谱。

抑癌基因启动子区异常甲基化与肾癌的发生发展密切相关。SOX7在肾癌中的表达情况及相关分子机制尚未明确指出。在本课题中，我们检测了SOX7在肾癌细胞系及肾癌组织中的表达水平和甲基化，发现与正常肾细胞系及癌旁正常肾组织相比，SOX7在肾癌细胞系及肾癌组织中的表达明显下降，通过研究分析我们验证引起其表达下调的主要机制为启动子区甲基化。此外，我们发现SOX7启动子区甲基化与肾癌的转移相关。接下来的细胞功能学实验证明过表达SOX7能抑制肿瘤细胞增殖、集落形成、细胞迁移、侵袭能力，并且能够促进细胞的凋亡及细胞周期(G2/M)的阻滞。并且验证了SOX7 逆转了EMT的进展，并中断了WNT/β-catenin信号通路。总之，我们的研究发现SOX7在肾癌中作为抑癌基因，常通过启动子区甲基化发挥功能。