ATF2 promotes urothelial cancer outgrowth via cooperation with androgen receptor signaling
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) corre...
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| Format: | Article |
| Language: | English |
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Bioscientifica
2018-11-01
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| Series: | Endocrine Connections |
| Subjects: | |
| Online Access: | https://ec.bioscientifica.com/view/journals/ec/7/12/EC-18-0364.xml |
| _version_ | 1818649044245807104 |
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| author | Satoshi Inoue Taichi Mizushima Hiroki Ide Guiyang Jiang Takuro Goto Yujiro Nagata George J Netto Hiroshi Miyamoto |
| author_facet | Satoshi Inoue Taichi Mizushima Hiroki Ide Guiyang Jiang Takuro Goto Yujiro Nagata George J Netto Hiroshi Miyamoto |
| author_sort | Satoshi Inoue |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-17T01:28:04Z |
| format | Article |
| id | doaj.art-cecb66f276b44ab0a051ad6c0c21e96a |
| institution | Directory Open Access Journal |
| issn | 2049-3614 2049-3614 |
| language | English |
| last_indexed | 2024-12-17T01:28:04Z |
| publishDate | 2018-11-01 |
| publisher | Bioscientifica |
| record_format | Article |
| series | Endocrine Connections |
| spelling | doaj.art-cecb66f276b44ab0a051ad6c0c21e96a2022-12-21T22:08:39ZengBioscientificaEndocrine Connections2049-36142049-36142018-11-0171213971408https://doi.org/10.1530/EC-18-0364ATF2 promotes urothelial cancer outgrowth via cooperation with androgen receptor signalingSatoshi Inoue0Taichi Mizushima1Hiroki Ide2Guiyang Jiang3Takuro Goto4Yujiro Nagata5George J Netto6Hiroshi Miyamoto7Department 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, USADepartment 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, USADepartment of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USADepartment 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, USADepartment 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, USADepartment 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, USADepartment 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, USADepartment 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, USAWe 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.https://ec.bioscientifica.com/view/journals/ec/7/12/EC-18-0364.xmlandrogen receptorATF2ERKneoplastic transformationprognosticatortumor progressionurothelial cancer |
| spellingShingle | Satoshi Inoue Taichi Mizushima Hiroki Ide Guiyang Jiang Takuro Goto Yujiro Nagata George J Netto Hiroshi Miyamoto ATF2 promotes urothelial cancer outgrowth via cooperation with androgen receptor signaling Endocrine Connections androgen receptor ATF2 ERK neoplastic transformation prognosticator tumor progression urothelial cancer |
| title | ATF2 promotes urothelial cancer outgrowth via cooperation with androgen receptor signaling |
| title_full | ATF2 promotes urothelial cancer outgrowth via cooperation with androgen receptor signaling |
| title_fullStr | ATF2 promotes urothelial cancer outgrowth via cooperation with androgen receptor signaling |
| title_full_unstemmed | ATF2 promotes urothelial cancer outgrowth via cooperation with androgen receptor signaling |
| title_short | ATF2 promotes urothelial cancer outgrowth via cooperation with androgen receptor signaling |
| title_sort | atf2 promotes urothelial cancer outgrowth via cooperation with androgen receptor signaling |
| topic | androgen receptor ATF2 ERK neoplastic transformation prognosticator tumor progression urothelial cancer |
| url | https://ec.bioscientifica.com/view/journals/ec/7/12/EC-18-0364.xml |
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