环氧化酶-2基因启动子区甲基化水平在子宫内膜异位症中的作用

doi:10.6040/j.issn.1671-7554.0.2016.942

摘要/Abstract

摘要： 目的检测环氧化酶-2(COX-2)基因启动子区CRE位点甲基化状况,探讨其在子宫内膜异位症(EMs)发生中的作用。方法收集南昌大学第一附属医院40例子宫内膜异位症患者的子宫内膜作为病例组,同期40例正常子宫内膜作为对照组,采用焦磷酸盐测序技术检测病例组和对照组子宫内膜组织中COX-2基因启动子区CRE位点甲基化频率;采用实时定量PCR及免疫组化技术分别检测病例组和对照组子宫内膜组织中COX-2 mRNA及蛋白的表达;分析COX-2基因启动子区CRE位点甲基化频率与COX-2表达水平的相关性。结果对照组内膜组织COX-2基因启动子区CRE位点的甲基化频率(40.81%±6.10%)显著高于病例组(14.74%±2.84%),P<0.05;而对照组COX-2 mRNA表达水平(0.98±0.37)及蛋白表达水平(1.00±0.73)显著低于病例组的mRNA表达水平(2.63±0.44)及蛋白表达水平(2.74±1.18),P均<0.05。随着COX-2基因启动子区CRE位点甲基化频率升高,COX-2基因表达水平下降,二者呈负相关(P<0.05)。结论 COX-2 基因启动子区CRE位点去甲基化与EMs患者在位内膜COX-2高表达相关,在EMs的发生、发展中具有重要作用,提示子宫内膜异位症是一种表观遗传性疾病。

关键词: 子宫内膜异位症, 环氧化酶-2, 甲基化, CRE位点

Abstract: Objective To study the methylation status of CRE sites in the cyclooxygenase-2(COX-2)gene promoter and its correlationship with endometriosis(EMs). Methods The endometrial tissues were collected from 40 women with laparoscopically confirmed EMs(case group), and 40 women without EMs(control group). The methylation status of COX-2 was examined by pyrosequencing. Quantitative real-time RT-PCR and immunohistochemistry were respectively performed to measure mRNA expression levels and protein levels of COX-2 in endometrial tissues. Finally, the correlation between COX-2 expression level and methylation frequencies of CRE sites were analyzed. Results The methylation frequencies of CRE sites in the COX-2 gene promoter was higher in the control group(40.81%±6.10%)than that in the case group(14.74%±2.84%), P<0.05. COX-2 mRNA levels(0.98±0.37)and protein levels(1.00±0.73)in the control group was significantly lower than the mRNA levels(2.63±0.44)and protein levels 山东大学学报 (医学版)55卷1期 -陈琦,等.环氧化酶-2基因启动子区甲基化水平在子宫内膜异位症中的作用 \=-(2.74±1.18)in the case group, both P<0.05. The correlation between COX-2 expression levels and methylation frequencies of CRE sites in the COX-2 gene promoter was negative(P<0.05). Conclusion The hypomethylation of CRE sites within the promoter of COX-2 may be responsible for the elevated gene expression in eutopic endometrium of EMs.

Key words: Endometriosis, Cyclooxygenase-2, CRE sites, Methylation

中图分类号:

R711.71

陈琦,李佳琪,郭智彬,贾惊宇,何林生. 环氧化酶-2基因启动子区甲基化水平在子宫内膜异位症中的作用[J]. 山东大学学报（医学版）, 2017, 55(1): 44-48.

CHEN Qi, LI Jiaqi, GUO Zhibin, JIA Jingyu, HE Linsheng. Role of methylation status of the cyclooxygenase-2 gene promoter in endometriosis[J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2017, 55(1): 44-48.

参考文献

[1] Bulun SE. Endometriosis[J]. N Engl J Med, 2009, 360(3): 268-279.
[2] Vinatier D, Cosson M, Dufour P. Is endometriosis an endometrial disease? [J]. Eur J Obstet Gynecol Reprod Biol, 2000, 91(2):113-125.
[3] Dubois RN, Abramson SB, Crofford L, et al. Cyclooxygenase in biology and disease[J]. FASEB J, 1998, 12(12):1063-1073.
[4] Chen Q, Zhang C, Chen Y, et al. Identification of endometriosis-related genes by representational difference analysis of cDNA[J]. Aust N Z J Obstet Gynaecol, 2012, 52(2):140-145.
[5] Huang F, Cao J, Liu Q, et al. MAPK/ERK signal pathway involved expression of COX-2 and VEGF by IL-1β induced in human endometriosis stromal cells in vitro[J]. Int J Clin Exp Pathol, 2013, 6(10):2129-2136.
[6] Khan KN, Kitajima M, Fujishita A, et al. Pelvic pain in women with ovarian endometrioma is mostly associated with coexisting peritoneal lesions[J]. Hum Reprod, 2013, 28(1):109-118.
[7] Cavalcanti V, Ponce TG, Mafra FA, et al. Evaluation of the frequency of G-765C polymorphism in the promoter region of the COX-2 gene and its correlation with the expression of this gene in the endometrium of women withendometriosis[J]. Arch Gynecol Obstet, 2016, 293(1):109-115.
[8] Feinberg AP. Phenotypic plasticity and the epigenetics of human disease[J]. Nature, 2007, 447(7143):433-440.
[9] Feinberg AP. Epigenetics at the epicenter of modern medicine[J]. JAMA, 2008, 299(11):1345-1350.
[10] Guo SW. Epigenetics of endometriosis[J]. Mol Hum Reprod, 2009, 15(10):587-607.
[11] Xu XL, Yu J, Zhang HY, et al. Methylation profile of the promoter CpG islands of 31 genes that may contribute to colorectal carcinogenesis[J]. World J Gastroenterol, 2004, 10(23):3441-3454.
[12] Lee S, Hwang KS, Lee HJ, et al. Aberrant CpG island hypermethylation of multiple genes in colorectal neoplasia[J]. Lab Invest, 2004, 84(7):884-893.
[13] Chow LW, Zhu L, Loo WT, et al. Aberrant methylation of cyclooxygenase-2 in breast cancer patients[J]. Biomed Pharmacother, 2005, 59(Suppl 2):S264-S267.
[14] Inoue H, Yokoyama C, Hara S, et al. Transcriptional regulation of human prostaglandin-endoperoxide synthase-2 gene by lipopolysaccharide and phorbol ester in vascular endothelial cells. Involvement of both nuclear factor for interleukin-6 expression site and cAMP response element[J]. J Biol Chem, 1995, 270(42):24965-24971.
[15] Inoue H, Tanabe T. Transcriptional role of the nuclear factor kappa B site in the induction by lipopolysaccharide and suppression by dexamethasone of cyclooxygenase-2 in U937 cells[J]. Biochem Biophys Res Commun, 1998, 244(1):143-148.
[16] Wang D, Chen Q, Zhang C, et al. DNA hypomethylation of the COX-2 gene promoter is associated with up-regulation of its mRNA expression in eutopic endometrium of endometriosis[J]. Eur J Med Res, 2012, 17(1):12.
[17] Zidan HE, Rezk NA, Alnemr AA, et al. COX-2 gene promoter DNA methylation status in eutopic and ectopic endometrium of Egyptian women with endometriosis[J]. J Reprod Immunol, 2015, 112: 63-67.
[18] Lee B, Dziema H, Lee KH, et al. CRE-mediated transcription and COX-2 expression in the pilocarpine model of statusepilepticus[J]. Neurobiol Dis, 2007, 25(1): 80-91.
[19] Mouawad CA, Mrad MF, El-Achkar GA, et al. Statins modulate cyclooxygenase-2 and microsomal prostaglandin E synthase-1 in human hepatic myofibroblasts[J]. J Cell Biochem, 2016, 117(5): 1176-1186.
[20] Kim SY, Hwang JS, Han IO. Tunicamycin inhibits Toll-like receptor-activated inflammation in RAW264.7 cells by suppression of NF-κB and c-Jun activity via a mechanism that is independent of ER-stress and N-glycosylation[J]. Eur J Pharmacol, 2013, 721(1-3): 294-300.
[21] Sharma-Walia N, George Paul A, Patel K, et al. NFAT and CREB regulate Kaposis sarcoma-associated herpesvirus-induced cyclooxygenase2(COX-2)[J]. J Virol, 2010, 84(24):12733-12753.
[22] Ohlsson Teague EM, Van der Hoek KH, Van der Hoek MB, et al. MicroRNA-regulated pathways associated with endometriosis[J]. Mol Endocrinol, 2009, 23(2):265-275.
[23] Zhou Y, Zeng C, Li X, et al. IGF-I stimulates ERβ and aromatase expression via IGF1R/PI3K/AKT-mediated transcriptional activation inendometriosis[J]. J Mol Med(Berl), 2016, 94(8):887-897.
[24] Hibi K, Taguchi M, Nakayama H, et al. Molecular detection of p16 promoter methylation in the serum of patients with esophageal squamous cell carcinoma[J]. Clin Cancer Res, 2001, 7(10):3135-3138.
[25] Tomizawa Y, Kohno T, Kondo H, et al. Clinicopathological significance of epigenetic inactivation of RASSF1A at 3p21.3 in stage I lung adenocarcinoma[J]. Clin Cancer Res, 2002, 8(7):2362-2368.
[26] Fischer JR, Ohnmacht U, Rieger N, et al. Promoter methylation of RASSFIA, RARbeta and DAPK predict poor prognosis of patient, with malignant mesothelioma[J]. Lung Cancer, 2006, 54(1):109-116.

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