Involvement of obesity in carsinogenesis of uterine endometrial cancer

背景资料：雌激素受体第5外显子和第7外显子可变剪接体（△ 5，△ 7）在体外分别呈显性阳性和显性阴性，但它们是否与各种子宫内膜疾病有关，以及它们在体内的作用尚不清楚。本研究旨在研究这些受体在子宫内膜疾病中的作用。方法：采用定量RT-PCR方法检测96例正常子宫内膜、7例子宫内膜增生过长和52例子宫内膜癌组织中△ 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，我们还用EIA法检测了ER和PR蛋白。为探讨瘦素对Er α可变剪接的影响，将不同浓度的瘦素作用于子宫内膜癌细胞株石川，检测Wt、△ 5、△ 7 mRNA的表达。结果：正常子宫内膜中Wt、△ 5、△ 7 mRNA的表达均明显低于正常子宫内膜，差异有统计学意义（P <0.05）。 ...更多信息 △ 5、△ 7 mRNA的表达与Wt mRNA的表达不同，显示了月经周期的变化。△ 5、△ 7与WtmRNA的表达比值（△ 5/Wt、△ 7/Wt）在正常子宫内膜中均不超过1.0，而在子宫内膜息肉、子宫内膜增生症和子宫内膜癌组织中，△ 5/Wt分别有44%、43%和40%的病例高于正常子宫内膜。△ 7/Wt在子宫内膜癌中的高表达率为27%。而△ 5或△ 7在体内对PR表达起显性正或负作用的证据不明显。结论：正常人子宫内膜中△ 5和△ 7mRNA的表达受到严格的、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，它们可能被Wt的生理功能所掩盖。推测其调控因子和功能与体内Wt不同。△ 5或△ 7 mRNA表达异常在正常子宫内膜中很少发生，但在良性子宫内膜疾病和恶性子宫内膜疾病中均可发生。肥胖妇女绝经后，外周血清中高浓度的瘦素可作用于子宫内膜细胞，使△ 5表达增加。在子宫内膜癌的发生过程中，绝经后肥胖导致瘦素浓度升高，△ 5表达增加，可能在雌激素缺乏的情况下维持细胞活性。这为以后发生的不可逆的遗传学变化提供了基础。在子宫内膜癌组织中，这些受体的表达失调可能有助于肿瘤的进展。

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