ATF2 promotes urothelial cancer outgrowth via cooperation with androgen receptor signaling

Satoshi Inoue; Taichi Mizushima; Hiroki Ide; Guiyang Jiang; Takuro Goto; Yujiro Nagata; George J Netto; Hiroshi Miyamoto

doi:10.1530/EC-18-0364

Endocrine Connections (Nov 2018)

ATF2 promotes urothelial cancer outgrowth via cooperation with androgen receptor signaling

Satoshi Inoue,
Taichi Mizushima,
Hiroki Ide,
Guiyang Jiang,
Takuro Goto,
Yujiro Nagata,
George J Netto,
Hiroshi Miyamoto

Affiliations

Satoshi Inoue: Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, New York, USA; James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
Taichi Mizushima: Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, New York, USA; James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
Hiroki Ide: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
Guiyang Jiang: Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, New York, USA; James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA
Takuro Goto: Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, New York, USA; James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA
Yujiro Nagata: Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, New York, USA; James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA
George J Netto: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA
Hiroshi Miyamoto: Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, New York, USA; James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; Department of Urology, University of Rochester Medical Center, Rochester, New York, USA

DOI: https://doi.org/10.1530/EC-18-0364
Journal volume & issue: Vol. 7, no. 12
pp. 1397 – 1408

Abstract

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We investigated the functional role of ATF2, a transcription factor normally activated via its phosphorylation in response to phospho-ERK/MAPK signals, in the outgrowth of urothelial cancer. In both neoplastic and non-neoplastic urothelial cells, the expression levels of androgen receptor (AR) correlated with those of phospho-ATF2. Dihydrotestosterone treatment in AR-positive bladder cancer cells also induced the expression of phospho-ATF2 and phospho-ERK as well as nuclear translocation and transcriptional activity of ATF2. Meanwhile, ATF2 knockdown via shRNA resulted in significant decreases in cell viability, migration and invasion of AR-positive bladder cancer lines, but not AR-negative lines, as well as significant increases and decreases in apoptosis or G0/G1 cell cycle phase and S or G2/M phase, respectively. Additionally, the growth of AR-positive tumors expressing ATF2-shRNA in xenograft-bearing mice was retarded, compared with that of control tumors. ATF2 knockdown also resulted in significant inhibition of neoplastic transformation induced by a chemical carcinogen 3-methylcholanthrene, as well as the expression of Bcl-2/cyclin-A2/cyclin-D1/JUN/MMP-2, in immortalized human normal urothelial SVHUC cells stably expressing AR, but not AR-negative SVHUC cells. Finally, immunohistochemistry in surgical specimens demonstrated significant elevation of ATF2/phospho-ATF2/phospho-ERK expression in bladder tumors, compared with non-neoplastic urothelial tissues. Multivariate analysis further showed that moderate/strong ATF2 expression and phospho-ATF2 positivity were independent predictors for recurrence of low-grade tumors (hazard ratio (HR) = 2.956, P = 0.045) and cancer-specific mortality of muscle-invasive tumors (HR = 5.317, P = 0.012), respectively. Thus, ATF2 appears to be activated in urothelial cells through the AR pathway and promotes the development and progression of urothelial cancer.

Published in Endocrine Connections

ISSN: 2049-3614 (Online)
Publisher: Bioscientifica
Country of publisher: United Kingdom
LCC subjects: Medicine: Internal medicine: Specialties of internal medicine: Diseases of the endocrine glands. Clinical endocrinology
Website: http://www.endocrineconnections.com/

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