Keap1/Nrf2/HIF-1α通路在宫颈癌中的表达及临床意义研究
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摘要
目的探讨Keap1/Nrf2/HIF-1α通路在宫颈癌患者中的表达及临床意义。方法选择2017年3月～2018年10月江西省萍乡市湘雅萍矿合作医院治疗的40例宫颈癌患者作为研究对象,所有患者均行手术治疗,术中切除病灶组织及癌旁组织,获得新鲜标本。采用免疫组织化学法测定获得宫颈癌组织及癌旁组织的低氧诱导因子-1α(HIF-1α)、NF-E_2相关因子2(Nrf2)、Keap1阳性率。采用反转录-聚合酶链反应(RT-PCR)技术测定Keap1-Nrf2-HIF-lα基因通路表达量。结果宫颈癌组织中的HIF-1α、Nrf2、Keap1阳性率,均高于癌旁组织(P<0.05)。免疫组化下Nrf2主要表达于宫颈癌细胞核内,部分位于胞质内,而HIF-1α、Keap1在宫颈癌组织中多表达于细胞胞质内。宫颈癌组织中的Keap1/Nrf2/HIF-1α基因通路表达量,高于癌旁组织(P<0.05)。结论 Keap1/Nrf2/HIF-1a通路在宫颈癌中呈表达,可能参与了宫颈癌疾病发生和发展的过程。
Objective To explore the expression and clinical significance of Keap1/Nrf2/HIF-1α pathway in cervical cancer. Methods A total of 40 patients with cervical cancer treated in our hospital from March 2017 to October 2018 were selected as subjects in this study. All the patients were treated by surgery. The lesion tissue and adjacent tissues were removed during the operation, and fresh specimens were obtained. The positive rates of hypoxia-inducible factor-1α(HIF-1α), NF-E_2 related factor 2(Nrf2) and Keap1 in cervical cancer tissues and adjacent tissues were determined by immunohistochemistry. The expression of Keap1/Nrf2/HIF-1α gene pathway was determined by RT-PCR. Results The positive rates of HIF-1α, Nrf2 and Keap1 in cervical cancer tissues were higher than those in adjacent tissues(P<0.05). Under immunohistochemistry, Nrf2 was mainly expressed in the nucleus of cervical cancer cells, partially in the cytoplasm; while HIF-1α and Keap1 were mainly expressed in the cytoplasm of cervical cancer tissues. The expression of the Keap1/Nrf2/HIF-1α gene pathway was higher in cervical cancer tissues than that in the adjacent tissues(P<0.05). Conclusion The Keap1/Nrf2/HIF-1α pathway is expressed in cervical cancer and may be involved in the pathogenesis and development of cervical cancer.
Objective To explore the expression and clinical significance of Keap1/Nrf2/HIF-1α pathway in cervical cancer. Methods A total of 40 patients with cervical cancer treated in our hospital from March 2017 to October 2018 were selected as subjects in this study. All the patients were treated by surgery. The lesion tissue and adjacent tissues were removed during the operation, and fresh specimens were obtained. The positive rates of hypoxia-inducible factor-1α(HIF-1α), NF-E_2 related factor 2(Nrf2) and Keap1 in cervical cancer tissues and adjacent tissues were determined by immunohistochemistry. The expression of Keap1/Nrf2/HIF-1α gene pathway was determined by RT-PCR. Results The positive rates of HIF-1α, Nrf2 and Keap1 in cervical cancer tissues were higher than those in adjacent tissues(P<0.05). Under immunohistochemistry, Nrf2 was mainly expressed in the nucleus of cervical cancer cells, partially in the cytoplasm; while HIF-1α and Keap1 were mainly expressed in the cytoplasm of cervical cancer tissues. The expression of the Keap1/Nrf2/HIF-1α gene pathway was higher in cervical cancer tissues than that in the adjacent tissues(P<0.05). Conclusion The Keap1/Nrf2/HIF-1α pathway is expressed in cervical cancer and may be involved in the pathogenesis and development of cervical cancer.
引文
[1]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,2016,43(1):146-152.
[2]卢志刚,黄家彬,刘芸,等.醒脑静注射液对急性脑梗死Keap1-Nrf2/ARE氧化应激通路的影响[J].广东医学,2016,37(20):3127-3129.
[3]Abu-Alainin W,Gana T,Liloglou T,et al.UHRF1 regulation of the Keap1-Nrf2 pathway in pancreatic cancer contributes to oncogenesis[J].J Pathol,2016,238(3):423-433.
[4]马瑶,白雪,李煜,等.混合砷对Keap1抑制细胞Keap1/Nrf2-ARE和MAPK/ERK信号通路的影响[J].环境与职业医学,2017,34(11):999-1003.
[5]黄攀,陆瀚文,周峥嵘,等.Keap1、Nrf2和HO-1在大鼠应激性胃溃疡中的表达[J].江苏农业科学,2016,44(12):280-282.
[6]刘理静,钱红,尹辉明,等.中华猕猴桃果仁非饱和脂肪酸通过激活Keap1/Nrf2信号通路增强肺纤维化大鼠抗氧化能力[J].细胞与分子免疫学杂志,2016,32(4):479-483.
[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]王换换,申正杰,肖航,等.热应激对肝脏中Keap1-Nrf2信号通路及下游基因表达的影响[J].南京农业大学学报,2017,40(1):151-156.
[9]Sun X,Ou Z,Chen R,et al.Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells[J].Hepatology,2016,63(1):173-184.
[10]吉琳梅,沈宏春,樊均明.NRF2通路在慢性肾脏疾病发生发展中的作用研究进展[J].山东医药,2016,56(19):100-102.
[11]黄娟,廖君,彭熙炜,等.脑泰方对脑缺血/再灌注大鼠海马区Nrf2、HO-1和膜铁转运辅助蛋白表达的影响[J].中国药理学通报,2017,33(10):1467-1472.
[12]王朝阳,荆黎.核转录因子E2相关因子2和Keap1的分子结构和功能及其信号通路调控分子机制研究进展[J].中国药理学与毒理学杂志,2016,30(5):598-604.
[13]Best SA,Souza DPD,Kersbergen A,et al.Synergy between the KEAP1/NRF2 and PI3K pathways drives non-smallcell lung cancer with an altered immune microenvironment[J].Cell Metab,2018,27(4):935.
[14]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.
[15]姬卫秀,何诗依,严露,等.低氧、低氧训练对小鼠骨骼肌Nrf2/Keap1结合量和p-Nrf2表达的影响[J].中国体育科技,2017,53(4):114-118.
[16]叶海主,陈亚娟,赵文英,等.肿瘤细胞和耐药肿瘤细胞中FoxO3/Keap1/Nrf2通路的表达差异[J].中国临床药理学与治疗学,2017,22(8):859-865.
[17]王宇锋,刘旭,陈超,等.6-姜烯酚对结直肠癌细胞中Keap1/Nrf2通路及下游基因表达的影响[J].宁夏医科大学学报,2017,39(10):1127-1132.
[18]马瑶,白雪,李煜,等.混合砷对Keap1抑制细胞Keap1/Nrf2-ARE和MAPK/ERK信号通路的影响[J].环境与职业医学,2017,34(11):999-1003.
[19]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,2016,43(1):146-152.
[20]王换换,申正杰,肖航,等.热应激对肝脏中Keap1-Nrf2信号通路及下游基因表达的影响[J].南京农业大学学报,2017,40(1):151-156.
[2]卢志刚,黄家彬,刘芸,等.醒脑静注射液对急性脑梗死Keap1-Nrf2/ARE氧化应激通路的影响[J].广东医学,2016,37(20):3127-3129.
[3]Abu-Alainin W,Gana T,Liloglou T,et al.UHRF1 regulation of the Keap1-Nrf2 pathway in pancreatic cancer contributes to oncogenesis[J].J Pathol,2016,238(3):423-433.
[4]马瑶,白雪,李煜,等.混合砷对Keap1抑制细胞Keap1/Nrf2-ARE和MAPK/ERK信号通路的影响[J].环境与职业医学,2017,34(11):999-1003.
[5]黄攀,陆瀚文,周峥嵘,等.Keap1、Nrf2和HO-1在大鼠应激性胃溃疡中的表达[J].江苏农业科学,2016,44(12):280-282.
[6]刘理静,钱红,尹辉明,等.中华猕猴桃果仁非饱和脂肪酸通过激活Keap1/Nrf2信号通路增强肺纤维化大鼠抗氧化能力[J].细胞与分子免疫学杂志,2016,32(4):479-483.
[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]王换换,申正杰,肖航,等.热应激对肝脏中Keap1-Nrf2信号通路及下游基因表达的影响[J].南京农业大学学报,2017,40(1):151-156.
[9]Sun X,Ou Z,Chen R,et al.Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells[J].Hepatology,2016,63(1):173-184.
[10]吉琳梅,沈宏春,樊均明.NRF2通路在慢性肾脏疾病发生发展中的作用研究进展[J].山东医药,2016,56(19):100-102.
[11]黄娟,廖君,彭熙炜,等.脑泰方对脑缺血/再灌注大鼠海马区Nrf2、HO-1和膜铁转运辅助蛋白表达的影响[J].中国药理学通报,2017,33(10):1467-1472.
[12]王朝阳,荆黎.核转录因子E2相关因子2和Keap1的分子结构和功能及其信号通路调控分子机制研究进展[J].中国药理学与毒理学杂志,2016,30(5):598-604.
[13]Best SA,Souza DPD,Kersbergen A,et al.Synergy between the KEAP1/NRF2 and PI3K pathways drives non-smallcell lung cancer with an altered immune microenvironment[J].Cell Metab,2018,27(4):935.
[14]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.
[15]姬卫秀,何诗依,严露,等.低氧、低氧训练对小鼠骨骼肌Nrf2/Keap1结合量和p-Nrf2表达的影响[J].中国体育科技,2017,53(4):114-118.
[16]叶海主,陈亚娟,赵文英,等.肿瘤细胞和耐药肿瘤细胞中FoxO3/Keap1/Nrf2通路的表达差异[J].中国临床药理学与治疗学,2017,22(8):859-865.
[17]王宇锋,刘旭,陈超,等.6-姜烯酚对结直肠癌细胞中Keap1/Nrf2通路及下游基因表达的影响[J].宁夏医科大学学报,2017,39(10):1127-1132.
[18]马瑶,白雪,李煜,等.混合砷对Keap1抑制细胞Keap1/Nrf2-ARE和MAPK/ERK信号通路的影响[J].环境与职业医学,2017,34(11):999-1003.
[19]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,2016,43(1):146-152.
[20]王换换,申正杰,肖航,等.热应激对肝脏中Keap1-Nrf2信号通路及下游基因表达的影响[J].南京农业大学学报,2017,40(1):151-156.