标题：Keap1/Nrf2信号通路在非小细胞肺癌氧化应激机制中的作用

      作者：王兰荣 1，曹旸 1，张伟 2，刘萌萌 3，王晓翠 1，魏丽 3，李蕾 1    王兰荣 1，曹旸 1，张伟 2，刘萌萌 3，王晓翠 1，魏丽 3，李蕾 11.郑州市第三人民医院肿瘤内科，河南 郑州 450000；2.郑州人民医院影像科，河南 郑州 450000；3.郑州市第三人民医院病理科，河南 郑州 450000

      卷次： 2024年35卷1期

      【摘要】 目的 检测非小细胞肺癌(NSCLC)组织中Kelch样环氧氯丙烷相关蛋白-1 (Keap1)、核因子E2相关因子2 (Nrf2)蛋白表达水平，分析其与临床病理参数、氧化应激指标的相关性，为临床治疗提供潜在靶点。方法 选取2017年4月至2020年4月郑州市第三人民医院收治的100例NSCLC患者为研究对象，免疫组化法检测并比较癌组织、癌旁组织中Keap1、Nrf2蛋白表达水平；比较不同临床病理参数患者Keap1、Nrf2蛋白表达水平；比较不同Ke-ap1、Nrf2蛋白表达患者血清超氧化物歧化酶(SOD)、诱导型一氧化氮合酶(iNOS)、丙二醛(MDA)水平，并采用Spear-man法分析SOD、iNOS、MDA与临床病理参数的相关性，采用Pearson法分析SOD、iNOS、MDA与Keap1、Nrf2蛋白水平的的相关性；比较不同Keap1、Nrf2蛋白表达患者的生存率。结果 癌组织、癌旁组织Keap1蛋白阳性率分别为77.00%、53.00%，Nrf2蛋白阳性率分别为74.00%、45.00%，Keap1蛋白OD值分别为0.41±0.07、0.33±0.05，Nrf2蛋白OD值分别为 0.39±0.06、0.31±0.06，癌组织Keap1、Nrf2蛋白阳性率及OD值明显高于癌旁组织，差异均有统计学意义(P<0.05)；Keap1蛋白阳性表达与病理分级、T分期呈正相关(r=0.569、0.574，P<0.01)，Nrf2蛋白阳性表达与病理分级、T分期呈正相关(r=0.527、0.539，P<0.01)；Keap1蛋白阳性者、阴性者的血清 SOD水平分别为(86.78±9.14) U/mL、(115.07±12.13) U/mL，MDA水平分别为(4.42±0.82) mmol/L、(3.24±0.56) mmol/L，iNOS水平分别为(22.74±4.31) U/mL、(15.59±3.02) U/mL，Nrf2蛋白阳性者、阴性者血清SOD水平分别为(84.94±9.12) U/mL、(117.06±12.37) U/mL，MDA水平分别为(4.48±0.85) mmol/L、(3.21±0.52) mmol/L，iNOS水平分别为(23.02±4.28) U/mL、(15.64±3.10) U/mL，Keap1、Nrf2蛋白阳性者血清SOD水平明显低于阴性者，MDA、iNOS水平明显高于阴性者，差异均有统计学意义(P<0.05)；Keap1、Nrf2蛋白表达与 SOD呈负相关(r=-0.612、-0.614，P<0.01)，与MDA、iNOS呈正相关(rKeap1=0.609、0.614，P<0.01；rNrf2=0.610、0.608，P<0.01)；Keap1、Nrf2蛋白阳性表达者 3年生存率为85.71%、83.78%，明显低于阴性表达者的95.65%、100.00%，差异均有统计学意义(P<0.05)。结论 NSCLC组织中Keap1、Nrf2蛋白表达水平升高，且与病理分级、T分期密切相关，该信号通路活化可参与氧化应激反应过程，且对预判患者预后具有一定临床意义。
      【关键词】 非小细胞肺癌；氧化应激；Kelch样环氧氯丙烷相关蛋白-1；核因子E2相关因子 2；超氧化物歧化酶；诱导型一氧化氮合酶；丙二醛
      【中图分类号】 R734.2 【文献标识码】 A 【文章编号】 1003—6350（2024）01—0010—05

Role of Keap1/Nrf2 signaling pathway in the mechanism of oxidative stress in non-small cell lung cancer.
WANGLan-rong 1, CAO Yang 1, ZHANG Wei 2, LIU Meng-meng 3, WANG Xiao-cui 1, WEI Li 3, LI Lei 1. 1. Department of Oncology,Zhengzhou Third People's Hospital, Zhengzhou 450000, Henan, CHINA; 2. Department of Imaging, Zhengzhou People'sHospital, Zhengzhou 450000, Henan, CHINA; 3.Department of Pathology, Zhengzhou Third People's Hospital, Zhengzhou450000, Henan, CHINA
【Abstract】 Objective To detect the expression levels of Kelch-like epichlorohydrin-related protein-1 (Keap1)and nuclear factor E2 related factor-2 (Nrf2) proteins in non-small cell lung cancer (NSCLC) tissues, analyze their corre-lation with clinical pathological parameters and oxidative stress indicators, and provide potential targets for clinical treat-ment. Methods A total of 100 NSCLC patients admitted to Zhengzhou Third People's Hospital from April 2017 toApril 2020 were selected as the research subjects, and immunohistochemical method was used to detect and compare theexpression levels of Keap1 and Nrf2 proteins in cancer tissues and adjacent tissues. The expression levels of Keap1 andNrf2 proteins in patients with different clinical pathological parameters were compared. The levels of serum superoxidedismutase (SOD), inducible nitric oxide synthase (iNOS), and malondialdehyde (MDA) in patients with different Keap1and Nrf2 protein expressions were compared, and the correlation between SOD, iNOS, MDA and clinical pathologicalparameters was analyzed using Spearman's method. The correlation between SOD, iNOS, MDA and Keap1 and Nrf2 pro-tein levels was analyzed using Pearson's method. The survival rate of patients with different Keap1 and Nrf2 protein ex-pressions was compared. Results The positive rates of Keap1 protein in cancer tissue and adjacent tissue were 77.00%and 53.00%, respectively, and the positive rates of Nrf2 protein were 74.00% and 45.00%, respectively. The OD valuesof Keap1 protein were 0.41±0.07 and 0.33±0.05, respectively, and the OD values of Nrf2 protein were 0.39±0.06 and0.31±0.06, respectively. The positive rates and OD values of Keap1 and Nrf2 proteins in cancer tissue were significantlyhigher than those in adjacent tissues, and the differences were statistically significant (P<0.05). The positive expressionof Keap1 protein was positively correlated with pathological grading and T staging (r=0.569, 0.574, P<0.01), while thepositive expression of Nrf2 protein was positively correlated with pathological grading and T staging (r=0.527, 0.539, P<0.01). The serum SOD levels of Keap1 protein positive and negative individuals were (86.78±9.14) U/mL, (115.07±12.13) U/mL, MDA levels were (4.42±0.82) mmol/L, (3.24±0.56) mmol/L, and iNOS levels were (22.74±4.31) U/mL,(15.59±3.02) U/mL, respectively. The serum SOD levels of Nrf2 protein positive and negative individuals were (84.94±9.12) U/mL, (117.06±12.37) U/mL, MDA levels were (4.48±0.85) mmol/L, (3.21±0.52) mmol/L, and iNOS levels were(23.02±4.28) U/mL and (15.64±3.10) U/mL, respectively. The serum SOD levels of Keap1 and Nrf2 protein positive in-dividuals were significantly lower than those of negative individuals, while MDA and iNOS levels were significantlyhigher than those of negative individuals, with statistically significant differences (P<0.05). The expression of Keap1and Nrf2 proteins was negatively correlated with SOD (r=-0.612, -0.614, P<0.01), and positively correlated with MDAand iNOS (rKeap1=0.609, 0.614, P<0.01; rNrf2=0.610, 0.608, P<0.01). The 3-year survival rates of patients with positive ex-pression of Keap1 and Nrf2 proteins were 85.71% and 83.78%, significantly lower than 95.65% and 100.00% of thosewith negative expression (P<0.05). Conclusion The expression levels of Keap1 and Nrf2 proteins in NSCLC tissue areelevated and closely related to pathological grading and T staging. The activation of this signaling pathway can partici-pate in the oxidative stress response process and has certain clinical significance in predicting patient prognosis.
      【Key words】 Non-small cell lung cancer; Oxidative stress; Kelch-like epichlorohydrin-related protein-1; Nuclearfactor E2 related factor 2; Superoxide dismutase; Inducible nitric oxide synthase; Malondialdehyde