TIMP-4在正常子宫内膜和子宫内膜癌组织中的表达

Expression of matrix metalloproteinase-26 in human endometrium and endometrial carcinoma

目的研究TIMP-4在正常子宫内膜、子宫内膜增生及子宫内膜癌组织中的表达。方法根据组织学分级将子宫内膜癌组织(n=38)分为高分化组、中分化组和低分化组。子宫内膜增生组织又分为单纯型增生(n=8)和非典型增生(n=7)。正常子宫内膜组织(n=37)按28天月经周期将其分为月经早期、月经中期和月经晚期。所有标本进行免疫组化和RT-PCR检测。结果免疫组化分析表明TIMP-4蛋白主要定位于子宫内膜组织的腺上皮部分及肿瘤细胞中,其次为小血管壁及基质中。RT-PCR及免疫组化半定量分析表明TIMP-4从月经增殖期表达开始升高,月经中期达到高峰(P=0.002;P=0.001)后表达逐渐下降至月经晚期(P=0.00014;P<0.0001)。月经中期子宫内膜和增生子宫内膜组织TIMP-4表达差异无显著性,但在恶性肿瘤中其表达明显下降(P<0.01;P<0.0001)。由于TIMP-4表达呈现出雌激素依赖关系,我们进一步检测各组织中ER-α表达情况,发现两者表达模式相似,因此我们推断ER-α参与了TIMP-4基因的调节。对TIMP-4启动区域的分析结果表明-930至-916位点与公认的ERE序列具有高度的同源性。结论TIMP-4蛋白主要表达于子宫内膜的上皮部分,高表达于正常子宫内膜中期和子宫内膜增生组织,在月经晚期和癌组织中表达下调。TIMP-4与ER-α表达模式相仿,TIMP-4启动区含有潜在的ERE序列。

[Objective] To examine the expression of TIMP-4 protein and mRNA in hyperplastic, premahgnant and malignant endometrial samples, and compare with normal endometrial tissue. [Methods] Endometrial carcinoma samples （n=38） were histologically classified as well, intermediately and poorly differentiated. Samples with hyperplastia （n=8） were classified as simple and complex with atypia. Normal endometrial specimens （n=37） were classified according to an ideal 28-day menstrual cycle and subsequently grouped in the early, middle, and late parts of the cycle. All samples were analyzed using immunohistochemistry and RT-PCR. [Results] Immunostaining localized TIMP-4 protein primarily in epithelial component of normal, hyperplastie and malignant samples. It was also found in the stroma and vessel walls. Semi-quantifieations with RT-PCR and immunohistochemistry revealed that TIMP-4 increased in the proliferative phase to a maximum in the mideyele （P =0.002; P =0.001 ）, and then decreased in the late part of the cycle （P =0.00014; P 〈0.0001）. Expression was comparable in the mideyle and hyperplastie （including atypical） endometrial samples, whereas lower levels were detected in the malignant tumors （P 〈0.01; P 〈0.0001）. Since the pattern of TIMP-4 expression mimicked that of ER-α, we searched the promoter region for a potential estrogen response element （ERE）. A sequence at position -930 to -916 had high homology to the consensus sequence of an ERE. ER-α was involved in regulation of the TIMP-4 gene. [Conclusions] TIMP-4 protein is primarily localized in the epithelial compartment of normal, hyperplastic, and malignant endometrial tissue. Expression was high in normal and hyperplastic endometria, but is downregulated in the late part of the cycle and in malignant tumors. The pattern of TIMP-4 expression mimics that of ER-α, and the promoter region of the TIMP-4 gene has a potential ERE.