Involvement of obesity in carsinogenesis of uterine endometrial cancer

背景：外显子5或外显子7交替剪接的雌激素受体（△5，△7）在体外分别表现为显性阳性或显性阴性，但它们是否或如何与各种子宫内膜疾病有关，以及它们在体内有什么功能尚不清楚。本研究旨在探讨这些受体在子宫内膜疾病中的作用。方法：采用定量RT-PCR方法，测定了正常人子宫内膜（96例）、子宫内膜增生（7例）和子宫内膜癌（52例）中△5、△7和野生型雌激素受体（Wt） mrna的表达。在子宫内膜癌组织中，我们也用EIA法测定了ER和PR蛋白。为了研究瘦素对Erα选择性剪接的影响，我们用不同浓度的瘦素培养石川子宫内膜癌细胞，检测Wt、△5、△7 mRNA的表达。结果：在正常人子宫内膜中，△5、△7 mRNA的表达更多地表现为月经周期，与Wt mRNA的表达不同。对Wt mrna的各表达比△5、△7（△5/Wt，△7/Wt）大于1.0的情况在正常子宫内膜中很少出现，但在子宫内膜息肉、子宫内膜增生和子宫内膜癌组织中，分别有44%、43%和40%的病例在正常子宫内膜中出现△5/Wt的高表达比。△7.27%的子宫内膜癌患者△7/Wt表达率较高。另一方面，没有显著的证据表明△5或△7对PR在体内的表达是显性的或负性的。瘦素可显著提高△5mrna的表达，且呈剂量依赖性和时间依赖性，并具有刺激细胞生长的作用。结论：在正常人子宫内膜中，△5和△7 mRNA的表达受到严格而独立的调控。它们在体内具有一定的生理功能，但在雌激素充足的情况下，它们应该被Wt的生理功能所覆盖。体内的调节因子和功能与Wt不同。△5或△7 Mrna表达的失调在正常子宫内膜中很少发生，但不仅在良性子宫内膜疾病中也可能发生，在恶性子宫内膜疾病中也可能发生。肥胖女性在绝经后，外周血中高浓度的瘦素可作用于子宫内膜细胞，使△5的表达增加。在子宫内膜癌的癌变过程中，由于肥胖，绝经后瘦素浓度高，△5表达的增加被认为是在缺乏雌激素的情况下维持细胞活性的作用。它为随后不可逆转的致癌基因变化提供了基础。在子宫内膜癌组织中，这些受体的表达失调可能导致肿瘤的发展

Background: Exon 5 or exon 7 altematively spliced estrogen receptors (△5, △7) have been reported to act dominant positive or dominant negative respectively in vitro, but it is not certain whether or how they are concerned with variant kinds of endometrial disease and what function they have in vivo. This study was designed to examine the role of those receptors in endometrial disease., especially endometrial cancer and the concern of leptin in alternative splicing of themMethods: By quantitative RT-PCR methods, we measured △5, △7 and wild type estrogen receptor (Wt) mRNAs in normal human endometrial (n=96), endometrial hyperplasia (n=7) and endometrial cancer (n=52). In endometrial cancer tissue, we also measured ER and PR protein by EIA. To examine the effect of leptin on altemative splicing of Erα, Ishikawa endometrial cancer cell was cultured with variant concentration of leptin, and the expression of Wt, △5, △7 mRNA were measuredResults: In normal human endometrium, the expression … More of △5, △7 mRNAs showed menstrual cycle, which were different from that of Wt Mrna. The each expression ratio of △5, △7 against Wt mRNAs (△5/Wt, △7/Wt) over 1.0 seldom occur in normal endometrium but in endometrialpolyp, endometrial hyperplasia and endmetrial cancer tissue, 44%, 43% and 40% of the cases showed high expression ratio of △5/Wt over the range in normal endometrium. As for △7.27% of endometrial cancer cases showed high △7/Wt expression ratio. On the other hand, no remarkable evidence that △5 or △7 works as dominant positive or negative on the expression of PR in vivo. Leptin increased the expression of △5 mRNA significantly in a dose and time dependent manner, and it also showed the effect to stimulate the cell growthConclusions: In normal human endometrium, the expression of △5 and △7 Mrna were regulated strictly and independenthly. They have some physiological function in vivo, but they were suppsed to be covered by that of Wt in estrogen sufficient circumstances. The regulation factor(s) and the function were supposed to be different from those of Wt in vivo. The deregulation of △5 or △7 Mrna expression seldom occur in normal endometrium, but can occur not only in benign but also in malignant endometrial disease. In obesity women, after menopause, high concentration of leptin in peripheral serum can work on endometrial cells to increase the expression of △5. On carcinogenesis of endometrial cancer, after menopause, with high concentration of leptin due to obesity, the increse of △5 expression was supposed to work on maintaining cellular activity under estrogen deprived circumstances. It provided a base to the following irreversible genetic changes toward carcinogenesis. And in endometrial cancer tissue, the deregulated expression of those receptors may contribute to the advancing of the tumor Less