Androgen promotes squamous differentiation of atypical cells in cervical intraepithelial neoplasia via an ELF3‐dependent pathway

Author:

Matsumoto Takeo1,Suzuki Takuma1,Nakamura Mitsuhiro12,Yamamoto Megumi1,Iizuka Takashi1ORCID,Ono Masanori13,Kagami Kyosuke1,Kasama Haruki1,Kanda Tatsuhito1,Sakai Yuya1,Iwadare Junpei1,Matsuoka Ayumi1,Kayahashi Kayo1,Wakae Kousho4,Muramatsu Masamichi4,Kyo Satoru5ORCID,Yamamoto Yasuhiko6,Mizumoto Yasunari1ORCID,Daikoku Takiko7,Fujiwara Hiroshi1ORCID

Affiliation:

1. Department of Obstetrics and Gynecology, Graduate School of Medical Sciences Kanazawa University Kanazawa Ishikawa 920‐8641 Japan

2. Department of Obstetrics and Gynecology, Public Central Hospital of Matto Ishikawa Hakusan Japan

3. Department of Obstetrics and Gynecology Tokyo Medical University Tokyo 160‐0023 Japan

4. Department of Virology II National Institute of Infectious Diseases Tokyo 162‐8640 Japan

5. Department of Obstetrics and Gynecology Shimane University Faculty of Medicine Izumo Shimane 693‐8501 Japan

6. Departments of Biochemistry and Molecular Vascular Biology Kanazawa University Graduate School of Medical Sciences Kanazawa Ishikawa 920‐8640 Japan

7. Division of Animal Disease Model, Research Center for Experimental Modeling of Human Disease Kanazawa University Kanazawa Ishikawa 920‐8640 Japan

Abstract

AbstractBackgroundSince the human papillomavirus vaccines do not eliminate preexisting infections, nonsurgical alternative approaches to cervical intraepithelial neoplasia (CIN) have been required. We previously reported that FOXP4 (forkhead box transcription factor P4) promoted proliferation and inhibited squamous differentiation of CIN1‐derived W12 cells. Since it was reported that FOXP expressions were regulated by the androgen/androgen receptor (AR) complex and AR was expressed on the CIN lesions, in this study we examined the effects of androgen on CIN progression.MethodsSince AR expression was negative in W12 cells and HaCaT cells, a human male skin‐derived keratinocyte cell line, we transfected AR to these cell lines and investigated the effects of dihydrotestosterone (DHT) on their proliferation and squamous differentiation. We also examined the immunohistochemical expression of AR in CIN lesions.ResultsDHT reduced the intranuclear expression of FOXP4, attenuating cell proliferation and promoting squamous differentiation in AR‐transfected W12 cells. Si‐RNA treatments showed that DHT induced the expression of squamous differentiation‐related genes in AR‐transfected W12 cells via an ELF3‐dependent pathway. DHT also reduced FOXP4 expression in AR‐transfected HaCaT cells. An immunohistochemical study showed that AR was expressed in the basal to parabasal layers of the normal cervical epithelium. In CIN1 and 2 lesions, AR was detected in atypical squamous cells, whereas AR expression had almost disappeared in the CIN3 lesion and was not detected in SCC, suggesting that androgens do not act to promote squamous differentiation in the late stages of CIN.ConclusionAndrogen is a novel factor that regulates squamous differentiation in the early stage of CIN, providing a new strategy for nonsurgical and hormone‐induced differentiation therapy against CIN1 and CIN2.

Publisher

Wiley

Subject

Cancer Research,Radiology, Nuclear Medicine and imaging,Oncology

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