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Estrogen-independent role of ERα in ovarian cancer progression induced by leptin/Ob-Rb axis

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Abstract

Leptin induces ovarian cancer cell invasion via overexpression of MMP7, MMP9, and upA. In addition, the key role of ERα in leptin-increased cell growth was indicated. However, the influence of ER on leptin-mediated cell invasion remains still unknown. The present study was designed to evaluate the E2-independent effect of ERα/β on leptin-mediated cell invasion and cell proliferation in ovarian cancer. We utilized SKOV3 cancer (expressing OB-Rb and ERα/β, insensitive to estrogen) and OVCAR3 (expressing OB-Rb) cell lines to show the involvement of ER in leptin-mediated effects in an E2-independent manner. MTT, BrdU, and BD matrigel invasion assays were applied to analyze cell growth, proliferation, and invasion. The siRNA approach was used to confirm the role of ERα/β in leptin effects. Moreover, western blotting and Real-time PCR were employed to detect the OB-Rb, ER, MMP9/7, and upA proteins and mRNAs. Leptin, in the absence of E2, increased ERα expression in SKOV3 cells, which was attenuated using knockdown of OB-Rb gene by siRNA. The effect of leptin on the cell growth was promoted in the presence of PPT, but not in the presence of DNP and E2, which was lost when OB-Rb siRNA was transfected. Furthermore, ERα gene silencing and/or pre-incubation with ER antagonist (ICI 182,780, 10 nM) significantly reduced cell invasion and MMP9 expression stimulated by leptin. In conclusion, our findings demonstrated that ERα, but not ERβ, is involved in leptin-induced ovarian cancer in an E2-independent manner, providing new evidence for cancer progression in obesity-associated ovarian cancer.

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Acknowledgements

This project was supported by grants from Isfahan University of Medical Sciences (Project number 394343) and the Surgical Oncology Research Center, Mashhad University of Medical Sciences. We would like to thank all those who helped us during this project including Neyshabur, Mashhad, and Isfahan Universities of Medical Sciences and colleague at the Islamic Azad University of Neyshabur.

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Authors and Affiliations

  1. Non-communicable Disease Research Center, Neyshabur University of Medical Sciences, Neyshabur, Iran

    Ahmad Ghasemi

  2. Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran

    Ahmad Ghasemi

  3. Department of Physiology, School of Basic Science, Neyshabur Branch, Islamic Azad University, Neyshabur, Iran

    Jafar Saeidi

  4. Department of Biology, School of Basic Science, Neyshabur Branch, Islamic Azad University, Neyshabur, Iran

    Mahnaz Mohtashami

  5. Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

    Seyed Isaac Hashemy

  6. Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

    Seyed Isaac Hashemy

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  1. Ahmad Ghasemi
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Ghasemi, A., Saeidi, J., Mohtashami, M. et al. Estrogen-independent role of ERα in ovarian cancer progression induced by leptin/Ob-Rb axis. Mol Cell Biochem 458, 207–217 (2019). https://doi.org/10.1007/s11010-019-03544-5

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