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The endocrine disruptor bisphenol A promotes nuclear ERRγ translocation, facilitating cell proliferation of Grade I endometrial cancer cells via EGF-dependent and EGF-independent pathways

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Abstract

Endocrine disruptors have become a global social and public health problem since the late 1980s. Bisphenol A (BPA) has a steroid-like skeleton similar to estrogen and progesterone, and is an endocrine disruptor that disturbs the physiological hormone balance. The potential involvement of BPA in malignancy of endometrial cancer cells caused by overexposure of steroid hormones remains incompletely understood. The present study aimed at understanding the regulatory mechanism underlying BPA-induced cell proliferation in hormone-sensitive endometrial cancer cells. BPA selectively and significantly induced cell proliferation of Grade I endometrial cancer cells such as HEC265 and Ishikawa cells. In HEC265 and Ishikawa cells, BPA induced nuclear translocation of estrogen-related receptor γ (ERRγ) in a time-dependent manner and increased expression of BPA/ERRγ-target genes. In Ishikawa cells, BPA promoted the influx of Ca2+ followed by epidermal growth factor (EGF) secretion to the extracellular space. Furthermore, EGF secreted from Ishikawa had an autocrine effect, leading to activation of the EGFR/ERK pathway. Contrastingly, in HEC265 cells, BPA increased the expression of BPA/ERRγ-target genes but did not affect Ca2+ mobilization EGF secretion. In conclusion, BPA induced cell proliferation via the BPA/ERRγ/EGF/EGFR/ERK signaling pathway in Ishikawa cells and contrastingly, in HEC265 cells, induced cell proliferation through the BPA/ERRγ signaling pathway.

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Acknowledgements

I would like to thank Yoichi Ueta, Yuuki Kamura, Misato Kawahara, Ryosuke Kawamura, Tatsuhiko Sugimoto, Erika Hatakeyama, Ayaka Hosoda, Jumpei Masuwa, Motonobu Mukai, Toshinori Mori, Kanae Ohashi, Saki Ohashi, Mami Ogawa, Suzuka Takahashi, Yui Teruya, Sayaka Fujita, Chisato Akiyama-Yamamuro, Mayu Kajioka, Manami Shiota, Yuri Sugano, Shihoko Sugino, Aoi Chiba, Kazuki Nobuhara, Yuki Matsubara, Syuto Miyake, Ryosuke Yamanaka, Yumi Matsuda, Misaki Mori, and Satoko Kodama for their contributions and helpful discussions. This research did not receive any specific grants from funding agencies in the public, commercial, or not-for-profit sectors.

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Authors and Affiliations

  1. Department of Chemical Technology, Graduate School of Science and Industrial Technology, Kurashiki University of Science and the Arts, 2640 Nishinoura Tsurajima-cho, Kurashiki, 712-8505, Japan

    Takahiro Yaguchi

  2. Department of Medical Laboratory Science, Graduate School of Health and Welfare Sciences, International University of Health and Welfare, 137-1 Enokizu, Okawa, Fukuoka, 831-8501, Japan

    Takahiro Yaguchi

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Correspondence to Takahiro Yaguchi.

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11010_2018_3410_MOESM1_ESM.tif

Supplementary Fig. 1 Nuclear translocation of ERRγ is not activated by vehicle treatment. HEC265 and Ishikawa cells were treated with vehicle control for the indicated times. Western blotting was carried out with nuclear and cytoplasmic fractions using anti-ERRγ, anti-Lamin or anti-β-actin antibody (n=3 independent experiments).—Supplementary material 1 (TIF 17230 KB)

11010_2018_3410_MOESM2_ESM.tif

Supplementary Fig. 2 BPA does not induce secretion of growth factors aFGF, bFGF, and HGF in HEC265 and Ishikawa cells. Both cell types were treated with BPA or vehicle control for 24 h, and conditioned medium was collected. Conditioned medium was immunoprecipitated with anti-aFGF, anti-bFGF, or anti-HGF antibody and Western blotting was carried out (n=3 independent experiments).—Supplementary material 2 (TIF 17926 KB)

11010_2018_3410_MOESM3_ESM.tif

Supplementary Fig. 3 ERRγ knockdown does not affect the expression of ERRs other than ERRγ in HEC265 and Ishikawa cells. HEC265 and Ishikawa cells were treated with ERRγ siRNA or non-coding control siRNA for 24 h followed by collecting total RNA, and RT-PCR was carried out (n=3 independent experiments).—Supplementary material 3 (TIF 17418 KB)

11010_2018_3410_MOESM4_ESM.tif

Supplementary Fig. 4 EGF knockdown did not affect the expression of ERRs in HEC265 and Ishikawa cells. HEC265 and Ishikawa cells were treated with EGF siRNA or non-coding control siRNA for 24 h. Total RNAs were collected 3 h after BPA stimulation and RT-PCR was carried out (b) (n=3 independent experiments). EGF mRNA expression was inhibited by EGF siRNA (a).—Supplementary material 4 (TIF 18208 KB)

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Yaguchi, T. The endocrine disruptor bisphenol A promotes nuclear ERRγ translocation, facilitating cell proliferation of Grade I endometrial cancer cells via EGF-dependent and EGF-independent pathways. Mol Cell Biochem 452, 41–50 (2019). https://doi.org/10.1007/s11010-018-3410-0

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