胃癌组织Keap-1、Nrf2蛋白表达及与患者远期生存的关系

Expression levels of Keap-1 and Nrf2 in gastric cancer and their correlation with the long-term survival

目的探讨胃癌组织Kelch样环氧氟丙烷相关蛋白-1(Keap-1)、核因子E2相关因子2(Nrf2)蛋白表达及其与患者远期生存的关系。方法回顾性分析2015年1月至2017年2月行根治性手术治疗的147例胃癌患者的临床资料,均于术中留取胃癌组织与癌旁正常组织(距癌≥5 cm),通过免疫组化法检测胃癌组织和相应癌旁正常组织中Keap-1、Nrf2蛋白表达情况并进行比较;术后随访5年,统计患者生存情况,采用Kaplan-Meier法绘制患者生存曲线,比较胃癌组织Keap-1、Nrf2蛋白表达阳性者与表达阴性者的中位生存时间;另依据术后5年随访期间患者生存情况,将其分为生存组和死亡组,比较2组胃癌组织中Keap-1、Nrf2蛋白表达,采用Cox比例风险回归模型分析影响胃癌患者远期生存的因素。结果胃癌组织中Keap-1、Nrf2蛋白阳性表达率均高于癌旁正常组织(P<0.05);147例胃癌患者在5年随访中,共死亡109例,生存38例,生存率25.85%;经Kaplan-Meier生存曲线分析显示,Keap-1蛋白阳性表达患者中位生存期低于Keap-1蛋白阴性表达患者(P<0.01),Nrf2蛋白阳性表达患者中位生存期低于Nrf2蛋白阴性表达患者(P<0.01)。死亡组患者胃癌组织中的Keap-1、Nrf2蛋白阳性表达率均高于生存组(P<0.05);经Cox比例风险回归模型分析,肿瘤≥4.5 cm、TNM分期为Ⅲ~Ⅳ期、低分化程度、淋巴结转移、术后未辅助化疗、Keap-1、Nrf2蛋白阳性表达均是影响胃癌患者远期生存的危险因素(P<0.05)。结论胃癌组织中Keap-1、Nrf2蛋白异常表达均与患者远期生存关系密切,为临床研究提供新方向;此外,肿瘤≥4.5 cm、低分化、TNM分期为Ⅲ~Ⅳ期、淋巴结转移、术后未辅助化疗也是影响胃癌患者远期生存情况的危险因素。临床工作中可针对上述危险因素提前预防,加强治疗,以改善患者远期生存情况。

Objective To detect the expression levels of Kelch-like Epichlorohydrin-associated protein 1(Keap1)and nuclear factor E2-related factor 2(Nrf2)in gastric cancer tissues and their correlation with the long-term survival.Methods The clinical data of 147 gastric cancer patients who underwent radical surgery in our hospital from January 2015 to February 2017 were analyzed retrospectively.Gastric cancer tissues and adjacent normal tissues(≥5cm from the cancer lesions)were intraoperatively collected for measuring expression levels of Keap1 and Nrf2 by immunohistochemistry.Gastric cancer patients were followed up for 5 years,and the survival curve was drawn by Kaplan-Meier method.The median survival of gastric cancer patients with positive and negative expressions of Keap1 and Nrf2 were compared.According to the survival recorded during the 5-year of follow-up,gastric cancer patients were divided into survival group and death group.Expression levels of Keap1 and Nrf2 in gastric cancer tissues of the two groups were compared.The factors affecting the long-term survival of gastric cancer patients with were analyzed by the Cox proportional hazards regression model.Results The positive expression rates of Keap1 and Nrf2 in gastric cancer tissues were significantly higher than those in adjacent normal tissues(P<0.05).During the 5-year of follow-up,109/147(74.15%)gastric cancer patients died and 38/147(25.85%)survived.Kaplan-Meier survival analysis showed that the median survival of gastric cancer patients with the positive expression of Keap1 or Nrf2 was significantly lower than those with a negative expression(both P<0.05).The positive expression rates of Keap1 and Nrf2 in gastric cancer tissues in the death group were significantly higher than those in the survival group(P<0.05).Cox proportional hazards regression model analysis showed that the tumor size≥4.5cm,TNM stagingⅢ~Ⅳ,poorly differentiated degree,lymph node metastasis,lack of postoperative adjuvant chemotherapy,and positive expressions of Keap1 and Nrf2 were all risk factors for the long-term survival of gastric cancer(all P<0.05).Conclusion Abnormally expressed Keap1 and Nrf2 in gastric cancer are closely correlated with the long-term survival of gastric cancer,which provides a new direction for clinical research.In addition,tumor size≥4.5cm,TNM stagingⅢ~Ⅳ,poorly differentiated degree,lymph node metastasis,lack of postoperative adjuvant chemotherapy,and positive expressions of Keap1 and Nrf2 were all risk factors for the long-term survival of gastric cancer.An active prevention of these risk factors and strengthen of clinical management contribute to improve the long-term survival of gastric cancer.