STAT3、MMPs及VEGF在子宫内膜异位症患者中的表达水平研究
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摘要
目的探讨子宫内膜异位症(EM)患者异位内膜组织中信号转导与转录激活因子3 (STAT3)、基质金属蛋白酶(MMPs)、血管内皮生长因子(VEGF)在疾病发生、发展中的调控过程及重要作用。方法采用实时聚合酶链反应、免疫印迹试验检测EM患者异位内膜、在位内膜以及非EM患者子宫内膜STAT3、p-STAT3、MMP-2、MMP-9及VEGF表达水平。结果①EM异位内膜组p-STAT3 mRNA和蛋白含量、STAT3活化水平(p-STAT3/STAT3)高于EM在位内膜组、对照组(P<0. 05);②EM异位内膜组MMP-2、MMP-9 mRNA和蛋白含量高于EM在位内膜组、对照组(P <0. 05);③ EM异位内膜组VEGF mRNA和蛋白含量高于EM在位内膜组、对照组(P <0. 01); EM在位内膜组VEGF mRNA和蛋白含量高于对照组(P <0. 05);④MMP-2、MMP-9蛋白含量与p-STAT3与蛋白含量呈正相关(r=3. 526、2. 843,P <0. 05); VEGF蛋白含量与pSTAT3蛋白含量呈正相关(r=4. 058,P<0. 05)。结论 EM患者异位内膜存在STAT3过度活化以及MMP-2、MMP-9、VEGF水平高表达,活化的高水平STAT3可能通过调节MMP-2、MMP-9以及VEGF的表达,从而促进细胞生长、抵抗凋亡、血管生成及侵袭。
Objective To explore the regulatory process and important roles of signal transducer and activator of transcription 3 (STAT3),matrix metalloproteinases (MMPs),and vascular endothelial growth factor (VEGF) in ectopic endometrium in pathogenesis and development of patients with endometriosis. Methods The expression levels of STAT3,p-STAT3,MMP-2,MMP-9,and VEGF in ectopic endometrium and eutopic endometrium of patients with endometriosis,and endometrium of patients without endometriosis were detected by PCR and Western blotting. Results The levels of p-STAT3 mRNA and protein,activation of STAT3 (p-STAT3/STAT3) in ectopic endometrium group were statistically significantly higher than those in eutopic endometrium group and control group (P< 0. 05). The levels of MMP-2 and MMP-9 mRNA and proteins in ectopic endometrium group were statistically significantly higher than those in eutopic endometrium group and control group (P<0. 05). The levels of VEGF mRNA and protein in ectopic endometrium group were statistically significantly higher than those in eutopic endometrium group and control group (P<0. 01). The levels of VEGF mRNA and protein in eutopic endometrium group were statistically significantly higher than those in control group (P<0. 05). The contents of MMP-2 and MMP-9 proteins were positively correlated with the content of p-STAT3 protein (r = 3. 526,2. 843,P<0. 05). The content of VEGF protein was positively correlated with the content of p-STAT3 protein (r = 4. 058,P<0. 05). Conclusion Overactivity of STAT3 and high levels of MMP-2,MMP-9,and VEGF are observed in ectopic endometrium of patients with endometriosis,high activated STAT3 level can promote cell growth,inhibit apoptosis,angiogenesis,and invasion by regulating the levels of MMP-2,MMP-9,and VEGF.
Objective To explore the regulatory process and important roles of signal transducer and activator of transcription 3 (STAT3),matrix metalloproteinases (MMPs),and vascular endothelial growth factor (VEGF) in ectopic endometrium in pathogenesis and development of patients with endometriosis. Methods The expression levels of STAT3,p-STAT3,MMP-2,MMP-9,and VEGF in ectopic endometrium and eutopic endometrium of patients with endometriosis,and endometrium of patients without endometriosis were detected by PCR and Western blotting. Results The levels of p-STAT3 mRNA and protein,activation of STAT3 (p-STAT3/STAT3) in ectopic endometrium group were statistically significantly higher than those in eutopic endometrium group and control group (P< 0. 05). The levels of MMP-2 and MMP-9 mRNA and proteins in ectopic endometrium group were statistically significantly higher than those in eutopic endometrium group and control group (P<0. 05). The levels of VEGF mRNA and protein in ectopic endometrium group were statistically significantly higher than those in eutopic endometrium group and control group (P<0. 01). The levels of VEGF mRNA and protein in eutopic endometrium group were statistically significantly higher than those in control group (P<0. 05). The contents of MMP-2 and MMP-9 proteins were positively correlated with the content of p-STAT3 protein (r = 3. 526,2. 843,P<0. 05). The content of VEGF protein was positively correlated with the content of p-STAT3 protein (r = 4. 058,P<0. 05). Conclusion Overactivity of STAT3 and high levels of MMP-2,MMP-9,and VEGF are observed in ectopic endometrium of patients with endometriosis,high activated STAT3 level can promote cell growth,inhibit apoptosis,angiogenesis,and invasion by regulating the levels of MMP-2,MMP-9,and VEGF.
引文
[1]蒋树龙,花宝金.JAK2/STAT3/SOCS3信号通路与肿瘤转移[J].中国肿瘤生物治疗杂志,2014,21(6):698-702.
[2]Joung YH,Na YM,Yoo YB,et al.Combination of AG490,a Jak2inhibitor,and methylsulfonylmethane synergistically suppresses bladder tumor growth via the Jak2/STAT3 pathway[J].Int J Oncol,2014,44(3):883-895.
[3]Okamoto M,Nasu K,Abe W,etal.Enhanced miR-210 expression promotes the pathogenesis of endometriosis through activation of signal transducer and activator of transcription 3[J].Hum Reprod,2015,30(3):632-641.
[4]胡娟,叶枫.子宫内膜异位症合并不孕症与STAT3基因多态性的相关性研究[J/OL].海南医学院学报,2016,22(10):948-950.
[5]冷金花,郎景和,赵学英,等.盆腔子宫内膜异位症病灶分布特点及其腹腔镜诊断准确性的评价[J].中华妇产科杂志,2006,54(2):111-113.
[6]殷震惠,杨华.VEGF、JAK2/STAT3信号通路与妇科疾病的关系[J].国际妇产科学杂志,2016,43(6):708-712.
[7]黄三秀.血清缺氧诱导因子-α及JAK蛋白水平在子宫内膜异位症中的诊断价值[J].实用临床医药杂志,2016,20(9):70-72.
[8]黄蓉,王玲,刘新琼,等.STAT3基因多态性与子宫内膜异位症合并不孕GnRH-a治疗效果的关系[J].中国妇幼保健,2017,32(3):545-548.
[9]吴松,郑桂霞,张艳辉,等.JAK2/STAT3信号通路与子宫内膜异位症发病机制相关性研究[J].中国继续医学教育,2016,8(30):51-53.
[10]刘彬,蒋晓东.STAT3表达与肿瘤血管生成及放射敏感性关系的研究进展[J].中国肿瘤临床,2015,42(10):535-539.
[11]庄梦斐,杨英,曹阳,等.子宫内膜异位症病理机制相关信号通路的研究进展[J/OL].生殖与避孕,2016,36(3):214-222,244.
[12]吴剑锋,沈佐君.JAK/STAT信号通路及其与肿瘤侵袭、转移的关系[J].生命的化学,2009,29(2):176-179.
[13]薛翔,刘红梅,邵旦兵,等.JAK/STAT信号通路调节机制的研究进展[J].现代生物医学进展,2015,15(11):2161-2165.
[14]范蕊,马楠.子宫内膜异位症患者血清中VEGF和IGF-Ⅰ的表达及其相关性[J].中国妇幼保健,2012,27(21):3328-3330.
[15]李燕,朱君,张煜.PI3K/AKT信号转导通路和VEGF在子宫内膜异位症中的表达[J].中国性科学,2017,26(4):45-47.
[16]刘儒彪,刘义,于岚,等.靶向siRNA阻断Wnt/β-catenin信号通路对子宫内膜异位症患者在位子宫内膜基质细胞VEGF、MMP-9表达的影响[J].华中科技大学学报(医学版),2016,45(1):6-11,26.
[2]Joung YH,Na YM,Yoo YB,et al.Combination of AG490,a Jak2inhibitor,and methylsulfonylmethane synergistically suppresses bladder tumor growth via the Jak2/STAT3 pathway[J].Int J Oncol,2014,44(3):883-895.
[3]Okamoto M,Nasu K,Abe W,etal.Enhanced miR-210 expression promotes the pathogenesis of endometriosis through activation of signal transducer and activator of transcription 3[J].Hum Reprod,2015,30(3):632-641.
[4]胡娟,叶枫.子宫内膜异位症合并不孕症与STAT3基因多态性的相关性研究[J/OL].海南医学院学报,2016,22(10):948-950.
[5]冷金花,郎景和,赵学英,等.盆腔子宫内膜异位症病灶分布特点及其腹腔镜诊断准确性的评价[J].中华妇产科杂志,2006,54(2):111-113.
[6]殷震惠,杨华.VEGF、JAK2/STAT3信号通路与妇科疾病的关系[J].国际妇产科学杂志,2016,43(6):708-712.
[7]黄三秀.血清缺氧诱导因子-α及JAK蛋白水平在子宫内膜异位症中的诊断价值[J].实用临床医药杂志,2016,20(9):70-72.
[8]黄蓉,王玲,刘新琼,等.STAT3基因多态性与子宫内膜异位症合并不孕GnRH-a治疗效果的关系[J].中国妇幼保健,2017,32(3):545-548.
[9]吴松,郑桂霞,张艳辉,等.JAK2/STAT3信号通路与子宫内膜异位症发病机制相关性研究[J].中国继续医学教育,2016,8(30):51-53.
[10]刘彬,蒋晓东.STAT3表达与肿瘤血管生成及放射敏感性关系的研究进展[J].中国肿瘤临床,2015,42(10):535-539.
[11]庄梦斐,杨英,曹阳,等.子宫内膜异位症病理机制相关信号通路的研究进展[J/OL].生殖与避孕,2016,36(3):214-222,244.
[12]吴剑锋,沈佐君.JAK/STAT信号通路及其与肿瘤侵袭、转移的关系[J].生命的化学,2009,29(2):176-179.
[13]薛翔,刘红梅,邵旦兵,等.JAK/STAT信号通路调节机制的研究进展[J].现代生物医学进展,2015,15(11):2161-2165.
[14]范蕊,马楠.子宫内膜异位症患者血清中VEGF和IGF-Ⅰ的表达及其相关性[J].中国妇幼保健,2012,27(21):3328-3330.
[15]李燕,朱君,张煜.PI3K/AKT信号转导通路和VEGF在子宫内膜异位症中的表达[J].中国性科学,2017,26(4):45-47.
[16]刘儒彪,刘义,于岚,等.靶向siRNA阻断Wnt/β-catenin信号通路对子宫内膜异位症患者在位子宫内膜基质细胞VEGF、MMP-9表达的影响[J].华中科技大学学报(医学版),2016,45(1):6-11,26.