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Gene expression changes and promoter methylation with the combined effects of estradiol and leptin in uterine tissue of the ovariectomized mice model of menopause.

Abstract：

:Substantial epidemiological studies have shown an association of obesity with the common gynecological malignancy, endometrial cancer. The relevant interactions and contribution of estradiol and the adipose cytokine, leptin, in endometrial lesions are not completely understood. Suitable animal models to understand the physiological response of uterine tissue to the combined effects of estradiol-leptin are lacking. To investigate the effect of estradiol-leptin crosstalk on gene expression and associated altered pathways, we established an ovariectomized mouse model, treated with 17-β estradiol (0.1 µg/mouse subcutaenously., for every 12 h) and/or recombinant mouse leptin (1 μg/g Bwt intraperitoneally., for every 12 h) for 4 h, 20 h, and 40 h. Gene expressions by semi-quantitative RT-PCR, uterine tissue protein phosphorylation status by western blotting and promoter methylation were analyzed in estradiol, progesterone insufficient animals. Semi-quantitative RT-PCR demonstrated significantly increased expression of Esr, Igf1, Igfbp3, Vegfr1, and Vegf, and significantly decreased expression of Mmp9 after co-treatment with estradiol and leptin, indicating a common transcriptional network regulated by the treatments. Ovariectomy-induced histomorphological changes were only reversed by estradiol. Methylation-specific PCR, analyzing methylation of CpG sites of Vegfa, Pgr, and Igf1, revealed that transcriptional regulation after hormonal treatments is independent of methylation at the examined CpG sites. Western blot confirmed the increased expression of PSTAT-3 (Ser-727) and PERK1/2 proteins after estradiol + leptin treatment, confirming the estradiol + leptin cross-talk hypothesis. In conclusion, our in vivo studies determined specific gene expression and signaling protein changes, and further unraveled the molecular targets of estradiol + leptin that may perturb endometrial homeostasis and lead to endometrial hyperplasia development in the chronic stimulated state.

journal_name

Mol Biol Rep

journal_title

Molecular biology reports

authors

Shetty A,Venkatesh T,Tsutsumi R,Suresh PS

doi

10.1007/s11033-019-05116-8

subject

Has Abstract

pub_date

2020-01-01 00:00:00

pages

151-168

issue

eissn

0301-4851

issn

1573-4978

pii

10.1007/s11033-019-05116-8

journal_volume

pub_type

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Gene expression changes and promoter methylation with the combined effects of estradiol and leptin in uterine tissue of the ovariectomized mice model of menopause.