5-脂氧合酶基因变异促进食管癌发生发展的遗传分子机制研究

Our previous research found that 5-LO metabolic pathway is closely related to the development of esophageal cancer. 5-LO is an important functional gene involved in the development of esophageal cancer, and it will be a new target for the prevention and treatment of esophageal cancer. Furthermore 5-LO rs2228065 polymorphism is associated with an increased risk of esophageal cancer. Especially in Mongolian patients with esophageal cancer, the mutation frequency of this polymorphism is 3.9% higher than that of the patient's average value, which are likely to be the genetic mechanisms of high incidence of esophageal cancer in Mongolian nationality. However，The exact clinical significance, the functions, molecular mechanisms of the gene mutation variations of 5-LO above still remain unknown, as well as their interactions with heavy drinking. Intending to profoundly analyze the molecular mechanisms of the individual differences of reaction for 5-LO inhibitor in esophageal cancer, a further and systematic study of those important scientific issues above is in need. It maybe can provides a new theoretical basis for the individualized treatment and a new indicator for early assessment, as well as a new way to explain the high incidence of esophageal cancer in Mongolian.

本课题组前期研究发现5-LO代谢通路与食管癌的发生发展密切相关，5-LO是一个参与食管癌发生发展的重要功能基因，会成为食管癌预防与治疗的新靶点。而且5-LO基因上存在一个SNP位点rs2228065，对比正常对照，食管癌组高出6.05倍，具有显著性差异（p<0.001）。蒙古族食管癌组比患者平均值还要高出3.9%，很可能是蒙古族食管癌高发的遗传机制之一。然而该变异引发食管癌发生的机制，发挥怎样功能，不同基因型对5-脂氧合酶抑制剂的反应如何，在血浆游离肿瘤DNA中是否也存在突变等诸多更深层次的新的重要科学问题均不清楚。基于此，我们提出了本项目，拟对上述科学问题展开深入系统研究，为食管癌患者的个体化治疗提供新的理论依据, 为早期评估食管癌发病风险提供新的指标, 为解释蒙古族食管癌高发提供新的途径。

本课题组前期研究发现ALOX5 rs2228065多态性与食管癌的发生发展密切相关，然而该变异引发食管癌发生的机制，发挥怎样功能，不同基因型对5-脂氧合酶抑制剂的反应如何，在血浆游离肿瘤DNA中是否也存在突变等诸多更深层次的新的重要科学问题均不清楚。本项目基于以上问题开展研究，发现在部分食管癌患者血浆游离肿瘤DNA中存在二次突变。临床检测食管癌患者尿液LTE4和血常规中全身炎症反应相关指标显著高于正常对照组。此外，按课题组制定的打分标准，发现遗传因素与环境因素的综合得分越高食管癌发病年龄越早，呈显著负相关。突变型ALOX5能促进细胞的增殖能力，而其抑制剂Zileuton对突变型ALOX5的抑制效果较野生型更加明显，提示突变型个体临床使用Zileuton的效果可能更佳。无论是小干扰RNA，还是ALOX5 抑制剂Zileuton都能促进铁死亡，抑制肿瘤的发生和发展，说明ALOX5是一个参与食管癌发生发展的重要功能基因，会成为食管癌预防与治疗的新靶点。ALOX5 rs2228065变异型的鉴定，为早期评估食管癌的发生风险及家族性食管癌提供了可能的分子依据，也为内蒙古赤峰地区蒙古族食管癌高发提供了新的理论依据。