直肠癌新辅助放化疗前后LGR5基因表达的变化及其与疗效的关系

Expression of the LGR5 gene in rectal cancer in response to neoadjuvant chemoradiotherapy

目的:探讨肿瘤干细胞标记基因LGR5在局部晚期直肠癌新辅助放化疗f放疗同时口服卡培他滨)前后表达的变化,及其对新辅助放化疗效果预测的作用。方法:收集2014年1月—2016年2月在新疆医科大学附属肿瘤医院接受新辅助放化疗并手术治疗的94例局部晚期直肠癌患者临床资料,对其新辅助放化疗前肠镜活检组织及新辅助放化疗后手术切除组织标本采用荧光定量PCR(qPCR)法检测LGR5 mRNA的表达,分析其在新辅助放化疗前后表达水平的变化及其与疗效的关系,采用Kaplan-Meier法进行生存分析,Log-rank法进行单因素预后分析和Cox回归进行多因素预后分析。结果:直肠癌患者接受新辅助放化疗后肿瘤病理退缩反应良好,肿瘤退缩有效率达87.2%,其中病理完全缓解率为18.1%。直肠癌癌组织中LGR5 mRNA的相对表达水平从新辅助放化疗前的14.396±9.924减少到手术后的8.847±6.664,总体表达水平显著下降(P<0.05)。放化疗后LGR5 mRNA表达上调者27例,表达下调者67例,表达下调组肿瘤病理退缩程度(TRG)和1、2年生存率均明显优于表达上调组(P<0.05)。单因素生存分析结果显示放化疗前血清CA19-9水平、临床分期、TRG分级和LGR5 mRNA表达差异为直肠癌预后的影响因素(P均<0.05);多因素分析表明放化疗前CA19-9水平和放化疗前后LGR5 mRNA表达差异是直肠癌预后的影响因素(P分别为0.013和0.015)。结论:新辅助放化疗可以诱导LGR5 mRNA表达的改变,检测其表达对于判断直肠癌预后及指导治疗具有参考价值,新辅助放化疗前后LGR5 mRNA表达变化和放化疗前CA19-9水平有可能成为预测局部晚期直肠癌新辅助放化疗效果的参考指标。

OBJECTIVE： To investigate changes in expression of the tumor stem cell marker LGR5 gene before and after neoadjuvant chemoradiotherapy and its predictive effect on neoadjuvant chemoradiation. METHODS： Ninety-four rectal cancer patients with preoperative chemoradiotherapy were enrolled in the Affiliated Tumor Hospital of Xinjiang Medical University between January 2014 and February 2016. Quantitative real-time PCR（qRT-PCR） method was used to determine the expression of LGR5 mRNA before and after neoadjuvant chemoradiotherapy. Overall survival（OS） rates were estimated by the Kaplan-Meier method and compared using the Log-rank test for univariate analysis. Cox regression analysis was performed to provide multivariate analysis. RESULTS： Tumor pathological regression reaction of rectal cancer after neoadjuvant chemoradiothepy was good. The efficiency was at 87.2%,and 18.1% patients achieved pathological complete response rate （pCR） after neoadjuvant chemoradiothepy. The expression level of LGR5 mRNA in rectal carcinoma tissues after chemoradiothepy （8.847±6.664） was significantly less than that before chemoradiothepy （14.396±9.924;P 〈 0.05）. The expression level of LGR5 mRNA after chemoradiothepy was up-regulated in 27 patients and down-regulated in 67 patients. Among them,the down-regulated group had significantly better tumor regression degree and 1,2 year-survival rates than that of the up-regulated group. Univariate analysis showed that several factors such as the CA19-9 levels before chemoradiothepy, clinical stage,grade of TRG and expression changes of LGR5 mRNA were significant prognostic factor for OS. CA19-9 levels before chemoradiothepy and expression changes of LGR5 mRNA showed significant differences in multivariate analysis. CONCLUSION： Neoadjuvant chemoradiotherapy caused changes in the expression of LGR5 mRNA. Our study shows that LGR5 mRNA expression changes before and after neoadjuvant chemoradiation and levels before chemoradiothepy had the prognostic potential on the effect of neoadjuvant chemoradiation for locally advanced rectal cancer.