Nrf2和Keap1蛋白在食管鳞状细胞癌中的表达及意义
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摘要
目的大量研究表明核因子E2相关因子2(Nrf2)和Kelch样环氧氯丙胺相关蛋白1(Keap1)与肿瘤发生发展相关。本研究旨在检测食管鳞状细胞癌中Nrf2、Keap1蛋白的表达及其与临床病理参数之间的关系,探讨其在食管癌发生、发展中的意义。方法选择2010年7月—2016年11月期间在新疆医科大学第一附属医院经手术治疗的食管癌患者174例,取食管癌组织标本及癌旁组织,使用免疫组织化学法,分别检测其中Nrf2及Keap1蛋白的表达水平并进行统计学分析,所有数据采用SPSS 17.0统计软件进行分析。结果 (1)Nrf2在食管鳞状细胞癌的表达水平显著高于癌旁正常组织(χ~2=21.259,P<0.001),Keap1在食管鳞状细胞癌的表达水平显著低于癌旁正常组织(χ~2=34.863,P<0.001)。(2)新疆不同民族之间Nrf2、Keap1的表达差异有统计学意义(Nrf2:χ~2=12.674,P=0.020;Keap1:χ~2=11.237,P=0.004)。(3)Nrf2的阳性表达与肿瘤淋巴结转移相关(χ~2=5.040,P=0.036),与食管癌组织分化程度也相关(χ~2=10.187,P=0.020)。Keap1阳性表达与肿瘤淋巴结转移相关(χ~2=6.916,P=0.010)和食管癌组织分化程度相关(χ~2=15.432,P<0.001)。(4)食管鳞状细胞癌中Nrf2和Keap1的表达具有相关性(相关系数r=0.219,P=0.031)。结论食管鳞状细胞癌的发生、发展和转移是多因素共同作用的结果,Nrf2、keap1蛋白参与食管鳞状细胞癌发生、发展过程,对临床进一步研究食管癌的预防和临床治疗及判断预后提供一定的新思路。
Objective Lots of researches had shown that nuclear factor erythroid-2 p45-related factor 2(Nrf2) and Kelch-like ECH-associated protein 1(Keap1) were correlated with the formation and development of tumors.This study was designed to detect the expression of Nrf2 and Keap1 protein in esophageal squamous cell carcinoma and explore its relationship with clinicopathological parameters,and to explore their role in the formation and development of esophageal cancer.Methods From July 2010 to November 2016,the cancer and adjacent tissues of 174 cases of esophageal cancer in the First Affiliated Hospital of Xinjiang Medical University were collected to detect the expression level of Nrf2 and Keap1 protein by using immunohistochemistry.The data was analyzed statistically by using SPSS 17.0 statistical software.Results(1) The expression level of Nrf2 in the cancer tissues of esophageal squamous cell carcinoma was significantly higher than that in adjacent normal tissues(χ~2= 21.259,P < 0.001),but the expression level of Keap1 in the cancer tissues was significantly lower than that in adjacent normal tissues(χ~2= 34.863,P < 0.001).(2) There was a statistically significant difference in the expression of Nrf2 and Keap1 among the different ethnic groups in Xinjiang(Nrf2:χ~2= 12.674,P = 0.020,Keap1:χ~2= 11.237,P = 0.004).(3) The positive expression of Nrf2 was associated with tumor lymph node metastasis(χ~2= 5.040,P = 0.036) and esophageal cancer tissue grading(χ~2= 10.187,P =0.020).The positive expression of Keap1 was associated with tumor lymph node metastasis(χ~2= 6.916,P = 0.010)and esophageal cancer tissue grading(χ~2= 15.432,P < 0.001).(4) There was a correlation between the expression of Nrf2 and Keap1 in esophageal squamous cell carcinoma(r = 0.219,P = 0.031).Conclusion In the formation,development and metastasis of esophageal squamous cell carcinoma,multiple factors may be involved,including Nrf2 and Keap1 proteins.This result will provide some new ideas for the further study of the prevention and clinical treatment of esophageal cancer and prognosis.
Objective Lots of researches had shown that nuclear factor erythroid-2 p45-related factor 2(Nrf2) and Kelch-like ECH-associated protein 1(Keap1) were correlated with the formation and development of tumors.This study was designed to detect the expression of Nrf2 and Keap1 protein in esophageal squamous cell carcinoma and explore its relationship with clinicopathological parameters,and to explore their role in the formation and development of esophageal cancer.Methods From July 2010 to November 2016,the cancer and adjacent tissues of 174 cases of esophageal cancer in the First Affiliated Hospital of Xinjiang Medical University were collected to detect the expression level of Nrf2 and Keap1 protein by using immunohistochemistry.The data was analyzed statistically by using SPSS 17.0 statistical software.Results(1) The expression level of Nrf2 in the cancer tissues of esophageal squamous cell carcinoma was significantly higher than that in adjacent normal tissues(χ~2= 21.259,P < 0.001),but the expression level of Keap1 in the cancer tissues was significantly lower than that in adjacent normal tissues(χ~2= 34.863,P < 0.001).(2) There was a statistically significant difference in the expression of Nrf2 and Keap1 among the different ethnic groups in Xinjiang(Nrf2:χ~2= 12.674,P = 0.020,Keap1:χ~2= 11.237,P = 0.004).(3) The positive expression of Nrf2 was associated with tumor lymph node metastasis(χ~2= 5.040,P = 0.036) and esophageal cancer tissue grading(χ~2= 10.187,P =0.020).The positive expression of Keap1 was associated with tumor lymph node metastasis(χ~2= 6.916,P = 0.010)and esophageal cancer tissue grading(χ~2= 15.432,P < 0.001).(4) There was a correlation between the expression of Nrf2 and Keap1 in esophageal squamous cell carcinoma(r = 0.219,P = 0.031).Conclusion In the formation,development and metastasis of esophageal squamous cell carcinoma,multiple factors may be involved,including Nrf2 and Keap1 proteins.This result will provide some new ideas for the further study of the prevention and clinical treatment of esophageal cancer and prognosis.
引文
[1]CHEN W,ZHENG R,BAADE P D,et al.Cancer statistics in China,2015[J].CA Cancer J Clin,2016,66(2):115-132.
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[4]张月明.新疆食管癌的分析[J].新疆医学院学报,1988,11(2):139-145.
[5]袁源,单春光,徐鸥,等.Nrf2和Keap1在喉癌组织中的表达及意义[J].临床耳鼻咽喉头颈外科杂志,2015,29(13):1148-1151.
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[8]周天域,吕鑫,陈雨桐,等.Nrf2的代谢调节作用与肿瘤的生长和增殖[J].中国细胞生物学学报,2017,39(3):381-388.
[9]TSAI J J,DUDAKOV J A,TAKAHASHI K,et al.Nrf2 regulates haematopoietic stem cell function[J].Nat Cell Biol,2013,15(3):309-316.
[10]DELGADO-BUENROSTRO N L,MEDINA-REYES E I,LASTRESBECKER I,et al.Nrf2 protects the lung against inflammation induced by titanium dioxide nanoparticles:A positive regulator role of Nrf2 on cytokine release[J].Environ Toxicol,2015,30(7):782-792.
[11]JI L,WEI Y,JIANG T,et al.Correlation of Nrf2,NQO1,MRP1,cmyc and p53 in colorectal cancer and their relationships to clinicopathologic features and survival[J].Int J Clin Exp Pathol,2014,7(3):1124-1131.
[12]苏昌亮,张庆华,黄磊.Nrf2在促进肿瘤生长及化学治疗耐药中的作用[J].医药导报,2015,34(3):354-357.
[13]BRYAN H K,OLAYANJU A,GOLDRING C E,et al.The Nrf2 cell defence pathway:Keap1-dependent and independent mechanisms of regulation[J].Biochem Pharmacol,2013,85(6):705-717.
[14]王昕海,巴桑,晋美,等.KEAP1基因突变调控Nrf2-ABCG2信号介导胃癌耐药的研究[J].外科理论与实践,2016,21(3):233-237.
[15]KHATRI R,SHAH P,CUHA R,et al.Aromatase inhibitor-mediated downregulation of INrf2(Keap1)leads to increased Nrf2 and resistance in breast cancer[J].Mol Cancer Ther,2015,14(7):1728-1737.
[16]LIMONCIEL A,JENNINGS P.A review of the evidence that ochratoxin A is an Nrf2 inhibitor:implications for nephrotoxicity and renal carcinogenicity[J].Toins(Basel),2014,6(1):371-379.
[2]TORRE L A,BRAY F,SIEGEL R L,et al.Global cancer statistics,2012[J].CA Cancer J Clin,2015,65(2):87-108.
[3]FAKHRIAN K,ORDU A D,LORDICK F,et al.Long-term outcomes of trimodality treatment for squamous cell carcinoma of the esophagus with cisplatin and/or 5-FU:more than 20 years'experience at a single institution[J].Strahlenther Onkol,2014,190(12):1133-1140.
[4]张月明.新疆食管癌的分析[J].新疆医学院学报,1988,11(2):139-145.
[5]袁源,单春光,徐鸥,等.Nrf2和Keap1在喉癌组织中的表达及意义[J].临床耳鼻咽喉头颈外科杂志,2015,29(13):1148-1151.
[6]EDGE S B,BYRD D R,COMPTON C C,et al.AJCC cancer staging manual[Z].严正,译.7版.(2010-01-01)[2015-03-01].http://max.book118.com/html/2015/1107/28773606.shtm.
[7]韩伦,赵琳.Nrf2-Keap1信号通路对肿瘤生物学行为影响的研究进展[J].山东医药,2016,56(36):103-105.
[8]周天域,吕鑫,陈雨桐,等.Nrf2的代谢调节作用与肿瘤的生长和增殖[J].中国细胞生物学学报,2017,39(3):381-388.
[9]TSAI J J,DUDAKOV J A,TAKAHASHI K,et al.Nrf2 regulates haematopoietic stem cell function[J].Nat Cell Biol,2013,15(3):309-316.
[10]DELGADO-BUENROSTRO N L,MEDINA-REYES E I,LASTRESBECKER I,et al.Nrf2 protects the lung against inflammation induced by titanium dioxide nanoparticles:A positive regulator role of Nrf2 on cytokine release[J].Environ Toxicol,2015,30(7):782-792.
[11]JI L,WEI Y,JIANG T,et al.Correlation of Nrf2,NQO1,MRP1,cmyc and p53 in colorectal cancer and their relationships to clinicopathologic features and survival[J].Int J Clin Exp Pathol,2014,7(3):1124-1131.
[12]苏昌亮,张庆华,黄磊.Nrf2在促进肿瘤生长及化学治疗耐药中的作用[J].医药导报,2015,34(3):354-357.
[13]BRYAN H K,OLAYANJU A,GOLDRING C E,et al.The Nrf2 cell defence pathway:Keap1-dependent and independent mechanisms of regulation[J].Biochem Pharmacol,2013,85(6):705-717.
[14]王昕海,巴桑,晋美,等.KEAP1基因突变调控Nrf2-ABCG2信号介导胃癌耐药的研究[J].外科理论与实践,2016,21(3):233-237.
[15]KHATRI R,SHAH P,CUHA R,et al.Aromatase inhibitor-mediated downregulation of INrf2(Keap1)leads to increased Nrf2 and resistance in breast cancer[J].Mol Cancer Ther,2015,14(7):1728-1737.
[16]LIMONCIEL A,JENNINGS P.A review of the evidence that ochratoxin A is an Nrf2 inhibitor:implications for nephrotoxicity and renal carcinogenicity[J].Toins(Basel),2014,6(1):371-379.