肺腺癌组织Nrf2和xCT蛋白表达及与顺铂耐药相关性分析

Correlation between the expression levels of Nrf2 and xCT protein in lung adenocarcinoma tissues and cisplatin resistance

目的分析肺腺癌组织中NF-E2相关因子(Nrf2)、胱氨酸/谷氨酸逆向转运蛋白溶质载体家族7成员11(xCT)蛋白表达水平与顺铂(DDP)耐药性的相关性。方法选取济南市第七人民医院2015-10-01-2018-10-01收治行外科根治手术切除的76例肺腺癌患者为研究对象,并在术后接受2~4次以铂类为主的化疗,分析Nrf2、xCT蛋白表达水平与临床病理特征、治疗反应以及细胞毒性指数(CI)间的相关性;另检测人肺腺癌顺铂耐药细胞系A549/DDP及其亲本细胞A549中Nrf2、xCT mRNA及蛋白表达水平。结果Nrf2蛋白表达水平与患者病理分期(χ^(2)=12.860,P=0.002)、分化程度(χ^(2)=8.111,P=0.017)和淋巴结转移(χ^(2)=5.258,P=0.022)有关;xCT蛋白表达水平与患者病理分期(χ^(2)=11.819,P=0.003)、分化程度(χ^(2)=7.578,P=0.023)和淋巴结转移(χ^(2)=9.881,P=0.002)有关。体外敏感性试验结果显示,76例肺腺癌组织中有27例DDP耐药,DDP耐药组患者的Nrf2阳性表达率为85.19%,高于DDP敏感组的48.98%(χ^(2)=9.670,P=0.002);xCT阳性表达率为92.59%,高于DDP敏感组的53.06%(χ^(2)=12.324,P<0.001);且Nrf2和xCT蛋白表达水平与CI呈正相关(r值分别为0.563和0.637,均P<0.05);近期化疗完全缓解+部分缓解肺腺癌组织中Nrf2阳性表达率为43.75%,低于稳定+进展组患者的75.00%(χ^(2) =7.667,P=0.006);xCT阳性表达率为46.88%,低于稳定+进展组患者的81.82%(χ^(2)=10.248,P=0.001)。A549/DDP细胞中Nrf2和xCT mRNA及蛋白表达水平高于A549细胞,均P<0.05。结论Nrf2和xCT蛋白表达与体外药敏试验以及肺腺癌细胞株耐药性具有较好的相关性,是预测肺腺癌原发性耐药的潜在指标。

Objective To analyze the correlation between expression levels of NF-E2 related factor(Nrf2)and cystine/glutamic acid reverse transport protein solute carrier family 7 member 11(xCT)protein in lung adenocarcinoma tissues and cisplatin(DDP)resistance.Methods Seventy-six patients with lung adenocarcinoma who underwent radical resection and were admitted to Jinan Seventh People’s Hospital were enrolled as the research objects from October 1,2015 to October 1,2018.All underwent platinum chemotherapy for two to four times after surgery.Correlation between the expression levels of Nrf2 and xCT protein and clinicopathological features,treatment response,cytotoxicity index(CI)was analyzed.The mRNA and protein expression levels of Nrf2 and xCT in human lung adenocarcinoma cisplatin-resistance cell line A549/DDP and its parental cell A549 were detected.Results The expression levels of Nrf2 protein were correlated with pathological staging(χ^(2) =12.860,P=0.002),differentiation degree(χ^(2)=8.111,P=0.017)and lymph node metastasis(χ^(2)=5.258,P=0.022).The expression levels of xCT protein were correlated with pathological staging(χ^(2)=11.819,P=0.003),differentiation degree(χ^(2)=7.578,P=0.023)and lymph node metastasis(χ^(2)=9.881,P=0.002).The results of in vitro sensitivity test showed that of the 76 patients,there were 27 cases with DDP resistance.The positive expression rates of Nrf2 and xCT in DDP resistance group were 85.19%and 92.59%,higher than those in DDP sensitivity group(48.98%and 53.06%),χ^(2)values were 9.670 and 12.324,Pvalues were 0.002 and<0.001.The expression levels of Nrf2 and xCT protein were positively correlated with CI(r=0.563 and 0.637,all P<0.05).The positive expression rates of Nrf2 in lung adenocarcinoma tissues of patients with complete remission+partial remission in short-term chemotherapy was 43.75%,lower than that with stable and progress status(75.00%),χ^(2)=7.667,P=0.006.The positive expression rates of xCT in lung adenocarcinoma tissues of patients with complete remission+partial remission in short-term chemotherapy was 46.88%,lower than that with stable and progress status 81.82%,χ^(2)=10.248,P=0.001.The expression levels of Nrf2 and xCT mRNA and protein in A549/DDP cells were higher than those in A549 cells,all P<0.05.Conclusion The expressions of Nrf2 and xCT protein are of good correlation with in vitro drug sensitivity test and drug resistance of lung adenocarcinoma cell lines,which are potential indexes to predict the primary drug resistance of lung adenocarcinoma.