FOXO1 as a tumor suppressor inactivated via AR/ERβ signals in urothelial cells

Hiroki Ide, Taichi Mizushima, Guiyang Jiang, Takuro Goto, Yujiro Nagata, Yuki Teramoto, Satoshi Inoue, Yi Li, Eiji Kashiwagi, Alexander S. Baras, George J. Netto, Takashi Kawahara, Hiroshi Miyamoto

研究成果: Contribution to journalArticle査読

8 被引用数 (Scopus)

抄録

Androgen receptor (AR) and estrogen receptor-β (ERβ) have been implicated in urothelial tumor outgrowth as promoters, while underlying mechanisms remain poorly understood. Our transcription factor profiling previously performed identified FOXO1 as a potential downstream target of AR in bladder cancer cells. We here investigated the functional role of FOXO1 in the development and progression of urothelial cancer in relation to AR and ERβ signals. In non-neoplastic urothelial SVHUC cells or bladder cancer lines, AR/ERβ expression or dihydrotestosterone/estradiol treatment reduced the expression levels of FOXO1 gene and induced those of a phosphorylated inactive form of FOXO1 (p-FOXO1). In chemical carcinogen-induced models, FOXO1 knockdown via shRNA or inhibitor treatment resulted in considerable induction of the neoplastic transformation of urothelial cells or bladder cancer development in mice. Similarly, FOXO1 inhibition considerably induced the viability, migration, and invasion of bladder cancer cells. Importantly, in FOXO1 knockdown sublines, an anti-androgen hydroxyflutamide or an anti-estrogen tamoxifen did not significantly inhibit the neoplastic transformation of urothelial cells, while dihydrotestosterone or estradiol did not significantly promote the proliferation or migration of urothelial cancer cells. In addition, immunohistochemistry in surgical specimens showed that FOXO1 and p-FOXO1 expression was down-regulated and up-regulated, respectively, in bladder tumor tissues, which was further associated with worse patient outcomes. AR or ERβ activation is thus found to correlate with inactivation of FOXO1 which appears to be their key downstream effector. Moreover, FOXO1, as a tumor suppressor, is likely inactivated in bladder cancer, which contributes in turn to inducing urothelial carcinogenesis and cancer growth.

本文言語英語
ページ(範囲)231-244
ページ数14
ジャーナルEndocrine-Related Cancer
27
4
DOI
出版ステータス出版済み - 4 1 2020
外部発表はい

All Science Journal Classification (ASJC) codes

  • 内分泌学、糖尿病および代謝内科学
  • 腫瘍学
  • 内分泌学
  • 癌研究

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