SFRP1基因甲基化在鼻咽癌转移中的作用和机制研究

The current treatment of nasopharyngeal carcinoma (NPC) is based on TNM clinical stage, while it cannot select patients with high risk of distant metastasis accurately. Therefore, It’s essential to find out new molecular prognostic markers, which can predict distant metastasis and guide individualized treatment of NPC. We have confirmed that SFRP1 gene promoter was hypermethylated in NPC by genome-wide methylation array screening method, which was related with higher risk of distant metastasis. The migration and invasion ability of NPC cells were inhibited in transfected CNE2 cell lines with SFRP1 over-expression plasmid. However, the exact mechanisms are unknown. In this project, firstly, we will examine the SFRP1 promoter methylation status in 300 NPC patients with matched clinical data, then analyse the its prediction value for distant metastasis. Then we will further study the functions and mechanisms of SFRP1 in NPC metastasis with different promoter methylation levels in vitro and in vivo, which may help to apply a novel molecular marker for clinical individualized therapy of NPC.

现行的鼻咽癌诊疗模式是基于TNM临床分期的分层治疗，然而其并不能很好地筛选出高转移风险的患者，远处转移仍然是鼻咽癌治疗失败的主要原因，提示需要寻找新的分子预后指标来预测鼻咽癌的远处转移及指导个体化治疗。我们前期实验初步提示：①采用全基因组甲基化芯片发现鼻咽癌组织中SFRP1基因启动子区存在高甲基化且基因表达量明显降低，与鼻咽癌远处转移相关；②瞬转SFRP1过表达质粒可抑制鼻咽癌细胞迁移和侵袭能力，但其在鼻咽癌转移中机制不详。本项目拟在此基础上，采用焦磷酸盐测序检测300例鼻咽癌SFRP1基因的甲基化状态，分析其对鼻咽癌远处转移的预测价值，为鼻咽癌个体化治疗提供分子基础；在鼻咽癌细胞株和转移瘤模型中研究SFRP1基因甲基化在鼻咽癌远处转移中的作用及机制，为鼻咽癌治疗提供潜在的新靶点。

现行的鼻咽癌诊疗模式是基于TNM临床分期的分层治疗，然而其并不能很好地筛选出高转移风险的患者，远处转移仍然是鼻咽癌治疗失败的主要原因，提示需要寻找新的分子预后指标来预测鼻咽癌的远处转移及指导个体化治疗。我们前期实验初步提示：①采用全基因组甲基化芯片发现鼻咽癌组织中SFRP1基因启动子区存在高甲基化且基因表达量明显降低，与鼻咽癌远处转移相关；②瞬转SFRP1过表达质粒可抑制鼻咽癌细胞迁移和侵袭能力，但其在鼻咽癌转移中机制不详。本项目在此基础上，采用焦磷酸盐测序检测244例鼻咽癌SFRP1基因的甲基化状态，确认SFRP1低表达与鼻咽癌患者总生存率、无疾病生存率及远处转移率明显相关，且是影响生存的独立预后因素，明确了其对鼻咽癌远处转移的预测价值，为鼻咽癌个体化治疗提供分子基础。鼻咽癌细胞中SFRP1表达显著下调。SFRP1启动子区域存在甲基化，SFRP1过表达可抑制鼻咽癌细胞体外增殖，迁移，侵袭和体内肺定植，。在鼻咽癌细胞中瞬转SFRP1后，b-Catenin，c-Myc和cyclin D1表达下调，提示SFRP1可能通过抑制NPC中Wnt / b-catenin信号通路抑制其生长和转移。以上研究初步明确了SFRP1基因甲基化在鼻咽癌远处转移中的作用及机制，为鼻咽癌治疗提供潜在的新靶点。