Affiliation:
1. 1Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
2. 2Department of Pathology, Obstetrics and Gynecology, Hospital of Fudan University, Shanghai, China
Abstract
Unopposed estrogen stimulation and insulin resistance are known to play important roles in endometrial cancer (EC), but the interaction between these two factors and how they contribute to endometrial lesions are not completely elucidated. To investigate the endometrial transcriptome profile and the associated molecular pathway alterations, we established an ovariectomized C57BL/6 mouse model treated with subcutaneous implantation of 17-β estradiol (E2) pellet and/or high-fat diet (HFD) for 12 weeks to mimic sustained estrogen stimulation and insulin resistance. Histomorphologically, we found that both E2 and E2 + HFD groups showed markedly enlarged uterus and increased number of endometrial glands. The endometrium samples were collected for microarray assay. GO and KEGG analysis showed that genes regulated by E2 and/or HFD are mainly responsible for immune response, inflammatory response and metabolic pathways. Further IPA analysis demonstrated that the acute phase response signaling, NF-κB signaling, leukocyte extravasation signaling, PPAR signaling and LXR/RXR activation pathways are mainly involved in the pathways above. In addition, the genes modulated reciprocally by E2 and/or HFD were also analyzed, and their crosstalk mainly focuses on enhancing one another’s activity. The combination analysis of microarray data and TCGA database provided potential diagnostic or therapeutic targets for EC. Further validation was performed in mice endometrium and human EC cell lines. In conclusion, this study unraveled the endometrial transcriptome profile alterations affected by E2 and/or HFD that may disturb endometrial homeostasis and contribute to the development of endometrial hyperplasia.
Subject
Endocrinology,Endocrinology, Diabetes and Metabolism,Internal Medicine
Reference37 articles.
1. Lipid-induced insulin resistance: unravelling the mechanism.;Lancet,2010
2. Met proto-oncogene and insulin-like growth factor binding protein 3 overexpression correlates with metastatic ability in well-differentiated pancreatic endocrine neoplasms.;Clinical Cancer Research,2004
3. Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms.;Nature Reviews Cancer,2004
4. Sunflower oil supplementation has proinflammatory effects and does not reverse insulin resistance in obesity induced by high-fat diet in C57BL/6 mice.;Journal of Biomedicine and Biotechnology,2012
5. Cancer statistics, 2017.;CA: A Cancer Journal for Clinicians,2017
Cited by
9 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献