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MIG-6 negatively regulates STAT3 phosphorylation in uterine epithelial cells

Oncogene volume 37, pages 255–262 (2018)Cite this article

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Abstract

Endometrial cancer is the most common malignancy of the female genital tract. Progesterone (P4) has been used for several decades in endometrial cancer treatment, especially in women who wish to retain fertility. However, it is unpredictable which patients will respond to P4 treatment and which may have a P4-resistant cancer. Therefore, identifying the mechanism of P4 resistance is essential to improve the therapies for endometrial cancer. Mitogen-inducible gene 6 (Mig-6) is a critical mediator of progesterone receptor (PGR) action in the uterus. In order to study the function of Mig-6 in P4 resistance, we generated a mouse model in which we specifically ablated Mig-6 in uterine epithelial cells using Sprr2f-cre mice (Sprr2fcre+Mig-6f/f). Female mutant mice develop endometrial hyperplasia due to aberrant phosphorylation of signal transducers and activators of transcription 3 (STAT3) and proliferation of the endometrial epithelial cells. The results from our immunoprecipitation and cell culture experiments showed that MIG-6 inhibited phosphorylation of STAT3 via protein interactions. Our previous study showed P4 resistance in mice with Mig-6 ablation in Pgr-positive cells (Pgrcre/+Mig-6f/f). However, Sprr2fcre+Mig-6f/f mice were P4-responsive. P4 treatment significantly decreased STAT3 phosphorylation and epithelial proliferation in the uterus of mutant mice. We showed that Mig-6 has an important function of tumor suppressor via inhibition of STAT3 phosphorylation in uterine epithelial cells, and the antitumor effects of P4 are mediated by the endometrial stroma. These data help to develop a new signaling pathway in the regulation of steroid hormones in the uterus, and to overcome P4 resistance in human reproductive diseases, such as endometrial cancer.

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Acknowledgements

We would like to thank Dr Diego H Castrillon (University of Texas Southwestern Medical Center, Dallas, TX, USA) for Sprr2f-cre mice. We would also like to thank Hanna E Teasley and Paige Wells for manuscript preparation. This work was supported by America Cancer Society, RSG-12-084-01-TBG and National Institutes of Health (NIH, HD084478) to JWJ and by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (NRF-2016R1D1A1B03934346) to JYY.

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Author notes

  1. J-Y Yoo and W S Yang: These authors contributed equally to this study.

Authors and Affiliations

  1. Department of Obstetrics, Gynecology and Reproductive Biology, Michigan State University, College of Human Medicine, Grand Rapids, MI, USA

    J-Y Yoo, W S Yang, J H Lee, B G Kim, T H Kim & J-W Jeong

  2. Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul, South Korea

    J-Y Yoo

  3. Department of Agricultural Biotechnology, Seoul National University, Seoul, South Korea

    W S Yang & J M Lim

  4. Department of Pathology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

    R R Broaddus

  5. Research Institute of Agriculture and Life Sciences, Seoul National University, Seoul, South Korea

    J M Lim

  6. Department of Women’s Health, Spectrum Health System, Grand Rapids, MI, USA

    J-W Jeong

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  1. J-Y Yoo
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Correspondence to T H Kim or J-W Jeong.

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Yoo, JY., Yang, W., Lee, J. et al. MIG-6 negatively regulates STAT3 phosphorylation in uterine epithelial cells. Oncogene 37, 255–262 (2018). https://doi.org/10.1038/onc.2017.335

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