右旋柠烯对DCBLD1易感基因型肺癌的预防作用研究

In the past few years, our team, which participated in the multicenter GWAS studies organized by the US National Institutes of Health of lung cancer in Asian populations, have identified a new 6q22. 2 susceptibility loci. A further study of a fine genomapping of the 760 pairs of lung cancer cases and controls, combining with further in vitro functional studies, we discovered that T/T genotype on DCBLD1 rs17079281 within the 6q22.2 loci may be associated with lung cancer through transcript factor YY1. We’ve also found that d-limonene, a natural “anticancer” agent, may affect lung cancer cell A549 clone. The purpose of this project is to further examine the preventive effect of D-Limonene in the carcinogenesis of lung cancer, particularly in patients carrying the special genotypes of DCBLD1 and other genes in the related pathways. Further in vitro functional studies will investigate whether D-limonene also affects lung cancer cells through susceptibility loci DCBLD1 and YY1. In addition, a specific carcinogens-induced lung caner mice model will be developed to explore such effects. We expect the results of this project will provide scientific evidence for using natural compounds such as D-Limonene for chemoprevention of lung cancer in target population in the Post-GWAS era.

课题组前期参与NIH组织亚洲多中心肺癌GWAS研究发现新的6q22.2易感区域的基础上，采用760对病例对照人群样本进行精细扫描与体外细胞学实验研究，发现该区域DCBLD1 rs17079281 T/T基因型可以通过结合转录因子YY1影响肺癌发病,且研究发现作为天然抗癌剂的右旋柠烯可影响肺癌细胞A549克隆形成。在此基础上，本项目将重点调查研究对象的右旋柠烯暴露情况，分析携带DCBLD1等特异基因型的人群中右旋柠烯对肺癌发生发展的影响；同时采用体外细胞学实验研究右旋柠烯通过影响DCBLD1易感基因型与YY1的作用而影响肺癌细胞功能。此外也将构建致癌物诱导小鼠肺癌模型，探索加入右旋柠烯的肺癌预防效果。本项目预期为下一步开展右旋柠烯的肺癌人群预防干预和临床治疗应用提供实验依据；为后-GWAS阶段提出人群针对性的病因学预防提供研究策略；也为天然化合物的肿瘤化学预防提供人群研究资料。

在课题组前期GWAS研究发现新的6q22.2易感区域的基础上，通过760对病例对照人群样本进行精细扫描与体外细胞学实验研究，并在4403例肺癌病人和5337例对照样本中进项了验证，发现该区域DCBLD1 rs17079281 T/T基因型可以通过结合转录因子YY1影响肺癌发病,且研究发现作为天然抗癌剂的右旋柠烯可影响肺癌细胞A549克隆形成。本项目将重点研究右旋柠烯对肺癌发生发展的影响；同时采用体外细胞学实验研究右旋柠烯是否通过影响DCBLD1易感基因型与YY1的作用而影响肺癌细胞功能。此外也构建了致癌物诱导小鼠肺癌模型，探索右旋柠烯的肺癌预防效果。实验结果显示右旋柠烯可显著抑制肺癌细胞的增殖、侵袭与迁移；裸鼠成瘤实验也得出右旋柠烯实验组的瘤体积和重量要小于对照组；在乌拉坦造模肺腺癌小鼠模型中，给予右旋柠烯干预，与对照组相比，右旋柠烯干预组具有更小和更少的肺部肿瘤。这表明右旋柠烯对于非吸烟肺癌具有一定的预防保护作用，而且能够通过自噬途径促进肺癌细胞的凋亡。本课题为下一步开展前瞻性的人群研究提供了可靠的实验基础，具有转化应用潜在的社会价值。