Involvement of obesity in carsinogenesis of uterine endometrial cancer

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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