Nrf2在非小细胞肺癌中的表达及临床意义
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摘要
目的探讨核转录因子E2相关因子2(Nrf2)在非小细胞肺癌(NSCLC)中的表达及临床意义。方法回顾性选取2013年7月至2016年12月在辽宁省肿瘤医院治疗的NSCLC患者组织标本72例,同时选取癌旁组织(距癌组织> 5 cm)标本作为对照。采用免疫组化染色和逆转录-聚合酶链反应(RT-PCR)检测Nrf2蛋白表达和mRNA表达,观察其与临床病理特征及预后的关系。结果 NSCLC组织Nrf2阳性表达率和Nrf2 mRNA表达分别为62. 50%和(1. 392±0. 223),明显高于癌旁组织(P <0. 05);肿瘤直径> 5 cm、TNM分期为Ⅲ～Ⅳ期、有淋巴结转移患者Nrf2蛋白阳性表达率分别为87. 88%、86. 36%和76. 19%,明显高于肿瘤直径≤5 cm、Ⅰ～Ⅱ期、无淋巴结转移患者(P <0. 05); Nrf2mRNA表达与患者临床病理特征无关(P> 0. 05); Nrf2蛋白表达和Nrf2 mRNA表达呈正相关(r_s=0. 366,P <0. 05);Nrf2蛋白阳性表达患者中位无进展生存时间和总生存时间分别为12个月(95%CI:9. 92～14. 08)和21个月(95%CI:19. 76～22. 25),明显低于Nrf2蛋白阴性表达者(P <0. 05)。结论 Nrf2在NSCLC患者中的表达明显升高,其与临床病理特征及预后有一定关系,值得进一步研究。
Objective To investigate the expression and clinical significance of Nrf2 in non-small cell lung cancer. Methods 72 specimens of NSCLC patients who were treated in our hospital from July 2013 to December 2016 were selected and the para cancerous tissue( From the cancer > 5 cm) was selected as the control,the expression of Nrf2 protein and Mrna was detected by immunohistochemical staining and RT-PCR,and the relationship with the clinicopathological features and prognosis was compared. Results The positive expression rate of Nrf2 and mRNA in NSCLC tissue were 62. 50% and 1. 392 ± 0. 223,which were significantly higher than that of para cancerous tissue( P < 0. 05). The expression of Nrf2 protein in patients with tumor diameter > 5 cm,TNM stage III-IV stage,lymph node metastasis were 87. 88%,86. 36% and76. 19%,significantly higher than the tumor diameter ≤5 cm,I ～ II,without lymph node metastasis( P < 0. 05). The expression of Nrf2 mRNA was not related to the clinicopathological features of the patients( P > 0. 05). The expression of Nrf2 protein was positively correlated with the expression of Nrf2 mRNA( rs= 0. 366,P < 0. 05). The median progression free survival time and overall survival time in patients with positive expression of Nrf2 protein were 12 months( 95% CI: 9. 92 ～ 14. 08) and 21 months( 95% CI: 19. 76 ～ 22. 25),which were significantly lower than that of negative expression of Nrf2 protein( P < 0. 05). Conclusion The expression of Nrf2 in NSCLC is obviously elevated,which has a certain relationship with the clinicopathological features and prognosis of the patients,is worth further study.
Objective To investigate the expression and clinical significance of Nrf2 in non-small cell lung cancer. Methods 72 specimens of NSCLC patients who were treated in our hospital from July 2013 to December 2016 were selected and the para cancerous tissue( From the cancer > 5 cm) was selected as the control,the expression of Nrf2 protein and Mrna was detected by immunohistochemical staining and RT-PCR,and the relationship with the clinicopathological features and prognosis was compared. Results The positive expression rate of Nrf2 and mRNA in NSCLC tissue were 62. 50% and 1. 392 ± 0. 223,which were significantly higher than that of para cancerous tissue( P < 0. 05). The expression of Nrf2 protein in patients with tumor diameter > 5 cm,TNM stage III-IV stage,lymph node metastasis were 87. 88%,86. 36% and76. 19%,significantly higher than the tumor diameter ≤5 cm,I ～ II,without lymph node metastasis( P < 0. 05). The expression of Nrf2 mRNA was not related to the clinicopathological features of the patients( P > 0. 05). The expression of Nrf2 protein was positively correlated with the expression of Nrf2 mRNA( rs= 0. 366,P < 0. 05). The median progression free survival time and overall survival time in patients with positive expression of Nrf2 protein were 12 months( 95% CI: 9. 92 ～ 14. 08) and 21 months( 95% CI: 19. 76 ～ 22. 25),which were significantly lower than that of negative expression of Nrf2 protein( P < 0. 05). Conclusion The expression of Nrf2 in NSCLC is obviously elevated,which has a certain relationship with the clinicopathological features and prognosis of the patients,is worth further study.
引文
[1]霍婷婷,贾金虎. EGFR基因检测在非小细胞肺癌诊疗应用中的新进展[J].癌症进展,2016,14(6):507-509,513.
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[9]赵静宇,汪梦霞,赵自明,等.基于Nrf2信号通路的三七总皂苷对Aβ25-35诱导PC12细胞凋亡的保护作用机制研究[J].中国药理学通报,2016,32(3):343-348,349.
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[13]白美玲,郝秀轻,李峰,等.食管鳞状上皮细胞癌中Keap1、Nrf2和HO-1的表达及临床病理意义[J].临床与实验病理学杂志,2016,32(8):914-917.
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[16]廖贵华,黄文峰. p62在喉癌Hep-2细胞化疗耐药中的作用[J].中国病理生理杂志,2017,33(6):1031-1037.
[17] Sepesi B,Nelson DB,Mitchell KG,et al. Prognostic value of PD-L1mRNA sequencing expression profile in non-small cell lung cancer[J]. Ann Thorac Surg,2018,105(6):1621-1626.
[18] Yoshino H,Murakami K,Nawamaki M,et al. Effects of Nrf2 knockdown on the properties of irradiated cell conditioned medium from A549human lung cancer cells[J]. Biomed Rep,2018,8(5):461-465.
[19] Karachaliou N,Berenguer J,Chaib I,et al. 66P PALB2 mRNA expression as a predictive marker in advanced non-small cell lung cancer(NSCLC)patients(p)treated with docetaxel-cisplatin[J]. J Thoracic Oncol,2018,13(4):S35.
[20] Mishra M,Jiang H,Chawsheen HA,et al. Nrf2-activated expression of sulfiredoxin contributes to urethane-induced lung tumorigenesis[J].Cancer Lett,2018,432:216-226.
[21] Kanwal M,Ding XJ,Song X,et al. MUC16 overexpression induced by gene mutations promotes lung cancer cell growth and invasion[J]. Oncotarget,2018,9(15):12226-12239.
[2]蒋小雯,王文娴,张沂平.埃克替尼治疗EGFR敏感突变的晚期非小细胞肺癌获益患者的临床分析[J].中国肺癌杂志,2016,19(4):200-206.
[3]卓越,梁冬. Twist和血管内皮生长因子在非小细胞肺癌组织中的表达及其与临床病理特征及预后的关系[J].中国老年学杂志,2017,37(18):4558-4560.
[4]周建平,李志芳,梁笠轩,等.肺癌细胞系中KEAP1与NRF2相互作用区域基因突变的检测[J].重庆医学,2017,46(5):590-592.
[5]沈晓宇,马锐.岩舒注射液雾化吸入联合奥沙利铂、吉西他滨化疗治疗非小细胞肺癌近期疗效研究[J].现代仪器与医疗,2016,22(1):110-112.
[6]刘长姣,李明春.非小细胞肺癌生物标志物在个体化治疗方面的研究进展[J].中国药理学与毒理学杂志,2016,30(4):375-380.
[7] Pandurangan AK,Saadatdoust Z,Esa NM,et al. Dietary cocoa protects against colitis-associated cancer by activating the Nrf2/Keap1 pathway[J]. BioFactors,2015,41(1):1-14.
[8]周冬辰,李龙芸,崔全才,等.变性高效液相色谱法分析中国人非小细胞肺癌、结直肠癌中表皮生长因子受体突变情况和临床意义[J].癌症进展,2006,4(5):462-466,433.
[9]赵静宇,汪梦霞,赵自明,等.基于Nrf2信号通路的三七总皂苷对Aβ25-35诱导PC12细胞凋亡的保护作用机制研究[J].中国药理学通报,2016,32(3):343-348,349.
[10]王媛媛,曹建,万建华,等.转录因子NF-E2相关因子在间歇性低氧大鼠心肌缺血/再灌注损伤中的保护机制[J].临床和实验医学杂志,2018,17(1):12-15.
[11]胡流芳,王迎,任汝静,等. Keap1-Nrf2/ARE信号通路的抗氧化应激作用及其调控机制[J].国际药学研究杂志,2016,(1):146-152,166.
[12]吴媛媛. Keap1/Nrf2信号通路对人肺鳞癌细胞生长、转移和耐药的影响[J].中国老年学杂志,2017,37(9):2123-2125.
[13]白美玲,郝秀轻,李峰,等.食管鳞状上皮细胞癌中Keap1、Nrf2和HO-1的表达及临床病理意义[J].临床与实验病理学杂志,2016,32(8):914-917.
[14] Moon EJ,Giaccia A. Dual roles of NRF2 in tumor prevention and progression:Possible implications in cancer treatment[J]. Free Radic Biol Med,2015,79:292-299.
[15]李军,熊琨,龚元,等.基于信号转导通路的姜黄素抗氧化机制研究进展[J].中草药,2016,47(13):2373-2380.
[16]廖贵华,黄文峰. p62在喉癌Hep-2细胞化疗耐药中的作用[J].中国病理生理杂志,2017,33(6):1031-1037.
[17] Sepesi B,Nelson DB,Mitchell KG,et al. Prognostic value of PD-L1mRNA sequencing expression profile in non-small cell lung cancer[J]. Ann Thorac Surg,2018,105(6):1621-1626.
[18] Yoshino H,Murakami K,Nawamaki M,et al. Effects of Nrf2 knockdown on the properties of irradiated cell conditioned medium from A549human lung cancer cells[J]. Biomed Rep,2018,8(5):461-465.
[19] Karachaliou N,Berenguer J,Chaib I,et al. 66P PALB2 mRNA expression as a predictive marker in advanced non-small cell lung cancer(NSCLC)patients(p)treated with docetaxel-cisplatin[J]. J Thoracic Oncol,2018,13(4):S35.
[20] Mishra M,Jiang H,Chawsheen HA,et al. Nrf2-activated expression of sulfiredoxin contributes to urethane-induced lung tumorigenesis[J].Cancer Lett,2018,432:216-226.
[21] Kanwal M,Ding XJ,Song X,et al. MUC16 overexpression induced by gene mutations promotes lung cancer cell growth and invasion[J]. Oncotarget,2018,9(15):12226-12239.