结直肠癌中NRF2的表达与肿瘤相关巨噬细胞的关系及临床意义

Relationship between NRF2 expression and tumor-associated macrophages in colorectal cancer and its clinical significance

目的检测核因子E2相关因子(nuclear factor erythroid2-related factor 2,NRF2)在结直肠癌(colorectal cancer,CRC)组织中的表达,探讨NRF2表达与肿瘤相关巨噬细胞(tumor-associatedmacrophages,TAMs)、上皮间质转化过程(epithelial-mesenchymal transition,EMT)的关系及临床病理意义。方法利用TIMER2.0数据库分析结直肠癌组织中NRF2表达以及NRF2与TAMs的关系;收集2017年5月至12月在山西省肿瘤医院被确诊为CRC的病例,采用免疫组织化学方法检测207例结直肠肿瘤组织和其中能收集到的90例癌旁正常组织中NRF2蛋白表达情况与临床病理特征的关系,以及EMT、TAMs分布情况。结果CRC中NRF2阳性率显著高于正常癌旁组织;肿瘤浸润前缘(tumor invasive front,TF)TAMs分布均高于肿瘤中心(tumor center,TC)。NRF2高表达与TNM分期、脉管癌栓、淋巴结转移、Vimentin蛋白以及TF中CD163+TAMs分布呈正相关。生存分析结果显示:NRF2低表达组生存期明显高于高表达组,是CRC患者的不良预后因素之一。结论NRF2在CRC患者中过度激活,通过靶向调控下游基因直接发挥作用促进上皮向间质转化过程;诱导巨噬细胞极化为M2型TAMs调控免疫反应间接发挥作用,从而增加癌症侵袭特性,缩短CRC患者生存时间。

Objective To detect the expression of nuclear factor erythroid2-related factor 2(NRF2)in colorectal cancer(CRC)tissues and to investigate the relationship between NRF2 expression and tumor-associated macrophages(TAMs),epithelial-mesen-chymal transition(EMT)and the clinicopathological significance.Methods NRF2 expression in colorectal cancer tissues and the rela-tionship between NRF2 and TAMs were analyzed using the TIMER2.0 database;cases diagnosed with CRC in Shanxi Cancer Hospital from May to December 2017 were collected,and NRF2 protein expression in 207 colorectal tumor tissues and 90 of the paracancerous normal tissues that could be collected were detected by immunohistochemistry.The relationship between NRF2 protein expression and clinicopathological features,as well as the distribution of EMT and TAMs in 207 colorectal tumor tissues and 90 normal paracancer tissues were examined by immunohistochemistry.Results NRF2 positivity rate was significantly higher in CRC than in normal para-neoplastic tissues,and the distribution of TAMs was higher in tumor invasive front(TF)than in tumor center(TC).The distribution of TAMs was positively correlated.Survival analysis showed that survival was significantly higher in the NRF2 low expression group than in the high expression group,which was one of the poor prognostic factors for CRC patients.Conclusion NRF2 is over-activated in CRC patients and acts directly to promote the epithelial-to-mesenchymal transition process by targeting and regulating downstream genes,inducing macrophages to polarize into M2-type TAMs to regulate immune responses indirectly,thereby increasing the invasive properties of cancer and shortening the survival time of CRC patients.