LGR5和ALDH1A1在非小细胞肺癌进展和预后中的作用

LGR5 and ALDH1A1 served as prognostic and predictive markers for non-small cell lung cancer

目的探讨富含亮氨酸的G蛋白偶联受体5（LGR5）和乙醛脱氢酶1A1（ALDH1A1）的表达在非小细胞肺癌（NSCLC）进展和预后中的作用,为NSCLC的诊疗寻找新靶点.方法选取2009年11月至2012年3月苏州大学附属第一医院NSCLC手术患者新鲜组织标本24例,石蜡标本109例.运用实时荧光定量PCR法检测LGR5和ALDH1A1在NSCLC组织和癌旁正常组织中的表达及相互关系;免疫组织化学染色法检测109例NSCLC组织和50例癌旁正常组织中LGR5和ALDH1A1的表达.应用Mann-Whitney u检验、χ^2检验、Pearson相关、Kaplan-Meier法及Cox比例风险回归模型分析数据.结果LGR5和ALDH1A1 mRNA在NSCLC组织中的表达高于对应癌旁正常组织（u值：150和74,均P〈0.01）,且二者表达具有相关性（r=0.416, P〈0.05）.免疫组织化学染色结果表明,LGR5和ALDH1A1在NSCLC组织中的阳性率分别为28.44%（31/109）和41.28%（45/109）,且在LGR5阳性表达的组织中,有24例（77.42%,24/31）ALDH1A1也阳性表达（r=0.388, P〈0.01）.另外,LGR5和ALDH1A1在高TNM分期NSCLC中的表达高于其在低TNM分期NSCLC中的表达（χ^2值：4.64和5.24,均P〈0.05）,二者在有淋巴结浸润NSCLC中的共表达高于其在无淋巴结浸润NSCLC中的共表达（χ^2=4.12,P〈0.05）.高表达LGR5或ALDH1A1的患者具有较差的预后（χ^2值：6.24和4.18,均P〈0.05）,而共表达LGR5和ALDH1A1的患者预后更不理想（χ^2=10.63,P〈0.01）.LGR5和ALDH1A1均为不良预后的独立危险因素[校正风险比分别为2.361（95% CI： 1.106～5.037）和2.306（95% CI： 1.101～4.830）,均P〈0.05].结论LGR5和ALDH1A1的表达与NSCLC的产生、转移和不良预后紧密相关,有望成为NSCLC靶向显像和靶向放射治疗的新靶点.

ObjectiveTo investigate the value of leucine-rich repeat-containing G protein coupled receptor 5 （LGR5） and aldehyde dehydrogenase 1A1 （ALDH1A1） in progression and prognosis of non-small-cell lung cancer （NSCLC）, in order to find new targets for NSCLC-targeted imaging and radiation therapy.MethodsFresh tissues （n=24） and paraffin embedding tissues （n=109） of patients with NSCLC were collected from the First Affiliated Hospital of Soochow University between November 2009 and March 2012. Quantitative real time-PCR was used for the investigation of expression of LGR5 and ALDH1A1 mRNA in 24 NSCLC patients. Immunohistochemistry （IHC） was used for detecting LGR5 and ALDH1A1 expressions in NSCLC tissues and adjacent normal tissues. Data were analyzed by Mann-Whitney u test, χ^2 test, Pearson correlation analysis, Kaplan-Meier method, Cox proportional hazards regression model.ResultsCompared with adjacent normal tissues, LGR5 and ALDH1A1 mRNA were frequently increased in NSCLC tissues （u values： 150, 74, both P〈0.01）, and the expression of LGR5 and ALDH1A1 mRNA was significantly correlated （r=0.416, P〈0.05）. Positive LGR5 and ALDH1A1 expression was defined in 28.44%（31/109） and 41.28%（45/109） of the NSCLC tumors, respectively. Further analysis indicated that 24 of the LGR5 positive samples （77.42%, 24/31） expressed ALDH1A1 （r=0.388, P〈0.01）. LGR5 and ALDH1A1 expressions in NSCLC with higher TNM stage were significantly higher than those in NSCLC with lower TNM stage （χ^2 values： 4.64, 5.24, both P〈0.05）. Coexpression of LGR5 and ALDH1A1 in NSCLC with lymph node metastasis was higher than that in NSCLC without lymph node metastasis （χ^2=4.12, P〈0.05）. High expression of LGR5 or ALDH1A1 was related to poor prognosis （χ^2 values： 6.24, 4.18, both P〈0.05）, and NSCLC patients with coexpression of LGR5 and ALDH1A1 had a poorer prognosis than the others （χ^2=10.63, P〈0.01）. Both of them were independent risk factors of a poorer prognosis （corrected hazard ratio （95% CI）： 2.361（1.106-5.037）, 2.306（1.101-4.830）; both P〈0.05）.ConclusionsThe expressions of LGR5 and ALDH1A1 are closely associated with the tumorigenesis, metastasis and poor prognosis of NSCLC. LGR5 and ALDH1A1 might be new targets for NSCLC-targeted tumor imaging and radiation therapy.