Department of Biosciences, Mangalore University, Mangalagangothri, Mangalore, 574 199, Karnataka, India.
School of Biotechnology, National Institute of Technology, Calicut, 673601, Kerala, India.
J Steroid Biochem Mol Biol. 2021 May;209:105843. doi: 10.1016/j.jsbmb.2021.105843. Epub 2021 Feb 12.
Obesity increases the risk of developing cancers for both males and females. This study investigated potential crosstalk between estradiol and leptin signaling pathways within the endometrium of high-fat-diet-induced obese ovariectomized mice to gain insight into possible links between obesity and endometrial cancer. We administered 17-β estradiol (0.2 μg/mouse subcutaneously) and/or recombinant mouse leptin (1 μg/g Bwt intraperitoneally.,) for 20 h to high-fat-diet-induced obese ovariectomized mice. The uterine tissues of experimental animals after treatments were studied by histological, immunohistochemical, quantitative real-time PCR (gene/miRNAs), and methylation-specific PCR analyses. Quantitative real-time PCR analysis revealed significantly increased expression of Cyclin d1, Esr1, Igf1, Igfbp2, Vegf, Oct4, and Pgr after estradiol and leptin co-treatment. Methylation-specific PCR results indicated that the hormonal dependent transcriptional regulation of Vegf, Igf1, and Pgr is independent of promoter methylation. The decreased expression of mmu- miR-204-5p after estradiol and leptin treatments correlated with the increased expression of long non-coding RNA Neat1. Insilico analysis confirmed the interaction of Neat1 and mmu- miR-204-5p and gene targets of mmu-miR-204-5p, including Igf1 were analyzed in this study. Immunohistochemical analyses revealed subcellular localization and increased expression of ESR, VEGF, phospho-Estrogen Receptor-α (pTyr537), and LEPR proteins following estradiol and leptin exposure. Overall, the data from our in vivo studies suggest the regulation of Neat1-mmu-miR-204-5p- Igf1 axis and associated gene expression changes in uterine tissue after estradiol and leptin co-treatment. In humans, long-term exposure to estradiol and leptin can alter endometrial homeostasis through the NEAT1-miR-204-5p-Igf1 axis and favor carcinogenic pathways, which provide mechanistic insight into the obesity-associated endometrial cancer.
肥胖增加了男性和女性患癌症的风险。本研究旨在探讨高脂肪饮食诱导肥胖去卵巢小鼠子宫内膜中雌二醇和瘦素信号通路之间的潜在串扰，以深入了解肥胖与子宫内膜癌之间的可能联系。我们给高脂肪饮食诱导肥胖去卵巢小鼠皮下注射 17-β 雌二醇（0.2 μg/只）和/或腹腔内注射重组小鼠瘦素（1 μg/g Bwt），共 20 小时。处理后的实验动物的子宫组织通过组织学、免疫组织化学、定量实时 PCR（基因/miRNAs）和甲基化特异性 PCR 分析进行研究。定量实时 PCR 分析显示，雌二醇和瘦素共同处理后，Cyclin d1、Esr1、Igf1、Igfbp2、Vegf、Oct4 和 Pgr 的表达显著增加。甲基化特异性 PCR 结果表明，Vegf、Igf1 和 Pgr 的激素依赖性转录调控与启动子甲基化无关。雌二醇和瘦素处理后 mmu-miR-204-5p 的表达下调与长链非编码 RNA Neat1 的表达增加相关。Insilico 分析证实了 Neat1 和 mmu-miR-204-5p 的相互作用，以及本研究中分析的 mmu-miR-204-5p 的基因靶标，包括 Igf1。免疫组织化学分析显示，雌二醇和瘦素暴露后，ESR、VEGF、磷酸化雌激素受体-α（pTyr537）和 LEPR 蛋白的亚细胞定位和表达增加。总的来说，我们的体内研究数据表明，在雌二醇和瘦素共同处理后，Neat1-mmu-miR-204-5p-Igf1 轴的调节以及子宫组织中相关基因表达的变化。在人类中，长期暴露于雌二醇和瘦素可能通过 NEAT1-miR-204-5p-Igf1 轴改变子宫内膜的稳态，并有利于致癌途径，为肥胖相关子宫内膜癌提供了机制上的见解。
