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Kawahara T, Kandori S, Kojima T, Mathis BJ, Shiga M, Nishiyama H. Feasibility of enzalutamide on patients with recurrent non-muscle-invasive bladder cancer with marker tumors: phase I study. BMC Res Notes 2025; 18:47. [PMID: 39891237 PMCID: PMC11786325 DOI: 10.1186/s13104-025-07128-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Accepted: 01/28/2025] [Indexed: 02/03/2025] Open
Abstract
OBJECTIVE Recent preclinical and retrospective clinical evidence shows that androgen receptor (AR)-mediated signals have significant roles in development of non-muscle invasive bladder cancer (NMIBC). Here, we conducted a single-center, phase I study to assess the feasibility and efficacy of enzalutamide in patients having recurrent NMIBC with marker tumors. Patients with NMIBC who cannot achieve complete transurethral resection (TUR) or with recurrence within a year after the TUR, were enrolled. The patients were administered oral enzalutamide at 160 mg dose, once daily for four weeks. Clinical response at the end of the treatment was evaluated using cystoscopy. RESULTS Of the six patients enrolled, two experienced multiple recurrences. All the patients received the planned administration of enzalutamide. Enzalutamide was tolerable and all patients were able to complete the planed treatment, although four patients experienced mild treatment-related adverse events (AEs), but AEs with grade 2 or more were not observed. As for efficacy, three patients showed no change while the remaining three showed disease progression. Immunohistochemical analysis did not showed the strong staining of AR in the latest tumors. This is the first clinical study on enzalutamide treatment for NMIBC patients. In this study, four weeks of enzalutamide administration was well tolerated, however showed no clinical response for non-strong staining of AR. TRIAL REGISTRATION University Hospital Medical Information Network UMIN000026520 (date registration: 2017/3/13).
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Affiliation(s)
- Takashi Kawahara
- Department of Urology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan
| | - Shuya Kandori
- Department of Urology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan.
| | | | - Bryan J Mathis
- International Medical Center, University of Tsukuba Affiliated Hospital, Tsukuba, Ibaraki, Japan
| | - Masanobu Shiga
- Department of Urology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan
| | - Hiroyuki Nishiyama
- Department of Urology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan
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Wang Y, Song Y, Peng Y, Han S, Qin C, Du Y, Xu T. Effects of androgen suppression therapy on the incidence and prognosis of bladder cancer: An updated systematic review and meta-analysis. Urol Oncol 2024; 42:266-274. [PMID: 38729866 DOI: 10.1016/j.urolonc.2024.04.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 03/29/2024] [Accepted: 04/11/2024] [Indexed: 05/12/2024]
Abstract
INTRODUCTION The influence of androgen suppression therapy (AST) on bladder cancer (BCa) remains controversial, as recent studies have not reached a consensus regarding the relationship between AST and the incidence or prognosis of BCa. MATERIALS AND METHODS We perform an updated systematic review and meta-analysis utilizing the most recent evidence to investigate the potential influence of AST on the incidence and prognosis of BCa. A comprehensive literature search was performed on the PubMed, Medline, Embase, Web of Science, and the Cochrane Library databases to include potentially eligible studies. Hazard ratios (HR) and odds ratios (OR) were used to calculate the incidence and prognosis of BCa. RESULTS This meta-analysis included 22 studies with 700,755 participants which investigated the impact of AST on the risk and prognosis of BCa. The pooled results revealed no significant relation between AST and a decreased incidence of BCa (OR: 0.92, 95%CI: 0.77-1.09, P = 0.342). Subgroup analysis reported that patients receiving 5-alpha reductase inhibitors (5-ARIs) exhibited a significantly lower risk of BCa (OR: 0.83, 95%CI: 0.75-0.91, P < 0.001), while androgen deprivation therapy did not show a significant reduction (OR: 1.00, 95%CI: 0.46-2.16, P = 0.995). AST may also significantly improve the recurrence-free survival of patients with BCa (HR: 0.69, 95%CI: 0.50-0.95, P = 0.023). We also detected a significant improvement in OS among BCa patients who received 5-ARIs compared to those without 5-ARIs (HR: 0.82, 95%CI: 0.68-0.99, P = 0.037). CONCLUSION No significant correlation was found between AST and a decreased BCa incidence, while 5-ARIs have demonstrated efficacy in reducing BCa occurrence. Moreover, patients who received AST demonstrated improved prognosis.
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Affiliation(s)
- Yulong Wang
- Department of Urology, Peking University People's Hospital, Beijing 100044, China; The Institute of Applied Lithotripsy Technology, Peking University People's Hospital, Beijing 100044, China
| | - Yuxuan Song
- Department of Urology, Peking University People's Hospital, Beijing 100044, China; The Institute of Applied Lithotripsy Technology, Peking University People's Hospital, Beijing 100044, China
| | - Yun Peng
- Department of Urology, Peking University People's Hospital, Beijing 100044, China; The Institute of Applied Lithotripsy Technology, Peking University People's Hospital, Beijing 100044, China
| | - Songchen Han
- Department of Urology, Peking University People's Hospital, Beijing 100044, China; The Institute of Applied Lithotripsy Technology, Peking University People's Hospital, Beijing 100044, China
| | - Caipeng Qin
- Department of Urology, Peking University People's Hospital, Beijing 100044, China; The Institute of Applied Lithotripsy Technology, Peking University People's Hospital, Beijing 100044, China
| | - Yiqing Du
- Department of Urology, Peking University People's Hospital, Beijing 100044, China; The Institute of Applied Lithotripsy Technology, Peking University People's Hospital, Beijing 100044, China
| | - Tao Xu
- Department of Urology, Peking University People's Hospital, Beijing 100044, China; The Institute of Applied Lithotripsy Technology, Peking University People's Hospital, Beijing 100044, China.
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Flores Monar GV, Reynolds T, Gordon M, Moon D, Moon C. Molecular Markers for Bladder Cancer Screening: An Insight into Bladder Cancer and FDA-Approved Biomarkers. Int J Mol Sci 2023; 24:14374. [PMID: 37762677 PMCID: PMC10531979 DOI: 10.3390/ijms241814374] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Revised: 09/10/2023] [Accepted: 09/13/2023] [Indexed: 09/29/2023] Open
Abstract
Bladder cancer is one of the most financially burdensome cancers globally, from its diagnostic to its terminal stages. The impact it imposes on patients and the medical community is substantial, exacerbated by the absence of disease-specific characteristics and limited disease-free spans. Frequent recurrences, impacting nearly half of the diagnosed population, require frequent and invasive monitoring. Given the advancing comprehension of its etiology and attributes, bladder cancer is an appealing candidate for screening strategies. Cystoscopy is the current gold standard for bladder cancer detection, but it is invasive and has the potential for undesired complications and elevated costs. Although urine cytology is a supplementary tool in select instances, its efficacy is limited due to its restricted sensitivity, mainly when targeting low-grade tumors. Although most of these assays exhibit higher sensitivity than urine cytology, clinical guidelines do not currently incorporate them. Consequently, it is necessary to explore novel screening assays to identify distinctive alterations exclusive to bladder cancer. Thus, integrating potential molecular assays requires further investigation through more extensive validation studies. Within this article, we offer a comprehensive overview of the critical features of bladder cancer while conducting a thorough analysis of the FDA-approved assays designed to diagnose and monitor its recurrences.
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Affiliation(s)
| | - Thomas Reynolds
- NEXT Bio-Research Services, LLC, 11601 Ironbridge Road, Suite 101, Chester, VA 23831, USA;
| | - Maxie Gordon
- BCD Innovations USA, 10606 Candlewick Road, Lutherville, MD 2109, USA
| | - David Moon
- HJM Cancer Research Foundation Corporation, 10606 Candlewick Road, Lutherville, MD 2109, USA
| | - Chulso Moon
- HJM Cancer Research Foundation Corporation, 10606 Candlewick Road, Lutherville, MD 2109, USA
- BCD Innovations USA, 10606 Candlewick Road, Lutherville, MD 2109, USA
- Department of Otolaryngology-Head and Neck Surgery, The Johns Hopkins Medical Institution, Cancer Research Building II, 5M3, 1550 Orleans Street, Baltimore, MD 21205, USA
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Rabbani S, Mattsson F, Lagergren J, Xie S. Use of 5α-reductase inhibitors and survival of oesophageal and gastric cancer in a nationwide Swedish cohort study. Acta Oncol 2023:1-6. [PMID: 37216488 DOI: 10.1080/0284186x.2023.2214681] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 05/11/2023] [Indexed: 05/24/2023]
Abstract
BACKGROUND We hypothesised that the use of the anti-androgenic drug 5α-reductase inhibitors (5-ARIs) improves survival in patients with oesophago-gastric cancer. METHODS This nationwide Swedish population-based cohort study included men who underwent surgery for oesophageal or gastric cancer between 2006-2015, with follow-up until the end of 2020. Multivariable Cox regression estimated hazard ratios (HR) for associations between 5-ARIs use and 5-year all-cause mortality (main outcome) and 5-year disease-specific mortality (secondary outcome). The HR was adjusted for age, comorbidity, education, calendar year, neoadjuvant chemo(radio)therapy, tumour stage, and resection margin status. RESULTS Among 1769 patients with oesophago-gastric cancer, 64 (3.6%) were users of 5-ARIs. Compared to non-users, users of 5-ARIs were not at any decreased risk of 5-year all-cause mortality (adjusted HR 1.13, 95% CI 0.79-1.63) or 5-year disease-specific mortality (adjusted HR 1.10, 95% CI 0.79-1.52). Use of 5-ARIs was not associated with any decreased risk of 5-year all-cause mortality in subgroup analyses stratified by categories of age, comorbidity, tumour stage, or tumour subtype (oesophageal or cardia adenocarcinoma, non-cardia gastric adenocarcinoma, or oesophageal squamous cell carcinoma). CONCLUSION This study did not support the hypothesis of improved survival among users of 5-ARIs after curatively intended treatment for oesophago-gastric cancer.
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Affiliation(s)
- Sirus Rabbani
- Upper Gastrointestinal Surgery, Department of Molecular medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Fredrik Mattsson
- Upper Gastrointestinal Surgery, Department of Molecular medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Jesper Lagergren
- Upper Gastrointestinal Surgery, Department of Molecular medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
- School of Cancer and Pharmaceutical Sciences, King's College London, United Kingdom
| | - Shaohua Xie
- Upper Gastrointestinal Surgery, Department of Molecular medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
- School of Public Health and Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, P.R. China
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5α-reductase inhibitors and the risk of bladder cancer in a large, population-based cohort. Urol Oncol 2023; 41:50.e11-50.e17. [PMID: 36319553 DOI: 10.1016/j.urolonc.2022.09.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 08/08/2022] [Accepted: 09/06/2022] [Indexed: 11/06/2022]
Abstract
PURPOSE The ability of 5α-reductase inhibitors (5ARI) to reduce the risk of new onset bladder cancer (BC) has been studied with variable results. Our objective was to conduct a retrospective cohort population-based study to evaluate the association between 5ARI use, BC diagnosis, and BC mortality. PATIENTS AND METHODS We used routinely collected health care data from Ontario, Canada. Men ≥66 years of age with a prescription for a 5ARI were matched to non-5ARI users. Matching was done using a propensity score of selected covariates to make 96 different covariates comparable. We measured 5 additional baseline variables which may have impacted the risk of future BC diagnosis: prior cystoscopy, urine cytology, urinalysis, gross hematuria episodes, and transurethral resection of a bladder lesion. Only the first period of continuous usage of 5ARIs was considered. The prespecified at-risk period for outcomes started 1 year after initiating therapy and ended at the last date of 5ARI exposure + 1 year. RESULTS We identified 93,197 men who initiated 5ARI therapy (52% dutasteride, and 48% finasteride) between 2003 and 2013 and matched them 1:1 to men who did not start a 5ARI. The median at-risk period for the 5ARI group was 1.68 years (interquartile range 1.00, 4.27). With adjustment for the variables related to prior BC investigations there was no significant difference in BC diagnosis (hazard ratio [HR] 1.05, 95% confidence interval [CI] 0.82-1.32) during the period of 0 to <2 years of 5ARI use; however, after ≥2 years of 5ARI use, the risk of BC diagnosis was significantly lower among the 5ARI group (HR 0.82, 95% CI 0.79-0.94). In a similarly adjusted model, BC mortality was lower among 5ARI users, but no longer statistically significant (HR 0.82, 95% CI 0.65, 1.02). When stratified by type of 5ARI, finasteride significantly reduced the risk of BC diagnosis after ≥2 years of continuous use (HR 0.86, 95% CI 0.76, 0.96); however, dutasteride did not (HR 0.92, 95% CI 0.83, 1.03). CONCLUSIONS In a large cohort of men, the use of a 5ARI was associated with a significantly decreased the risk of BC diagnosis after more than 2 years of continuous therapy.
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Plage H, Samtleben H, Hofbauer S, Kornienko K, Weinberger S, Bruch PG, Elezkurtaj S, Roßner F, Schallenberg S, Kluth M, Lennartz M, Blessin NC, Marx AH, Fisch M, Rink M, Slojewski M, Kaczmarek K, Ecke T, Hallmann S, Koch S, Adamini N, Minner S, Simon R, Sauter G, Klatte T, Schlomm T, Horst D, Zecha H. GATA3 expression loss is linked to stage progression but is unrelated to prognosis in muscle-invasive urothelial carcinoma of the bladder. Hum Pathol 2022; 130:10-17. [PMID: 36152841 DOI: 10.1016/j.humpath.2022.09.004] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 08/05/2022] [Accepted: 09/16/2022] [Indexed: 12/14/2022]
Abstract
The transcription factor GATA binding protein 3 (GATA3) is commonly used in surgical pathology as a diagnostic marker to distinguish urothelial carcinomas from other cancer entities. However, the clinical relevance of GATA3 expression in urothelial bladder cancer is not completely clarified. In this study, we investigated GATA3 immunostaining on 2710 urothelial bladder carcinomas on a tissue microarray platform by using two different antibodies to better understand its impact in relation to pathological parameters of disease progression and patient outcome. Nuclear GATA3 immunostaining was regularly seen in normal urothelium and found in 74%/82% of interpretable urothelial neoplasms depending on the antibody used. Within pTa tumors, the rate of GATA3 positive tumors decreased with advancing grade. GATA3 positivity was seen in 98.6%/99.8% of pTaG2 low-grade, 98.6%/100% of pTaG2 high-grade, and 94.9%/99.2% of pTaG3 high-grade tumors (P = .0002). As compared to pTa tumors, GATA3 positivity was markedly less common in muscle-invasive urothelial carcinoma (59.9%/71.6%; P < .0001). Within pT2-4 cancers, high-level GATA3 immunostaining was associated with the presence of lymph node metastasis (P = .0034), and blood vessel (P = .0290) or lymphatic invasion (P = .0005) but unrelated to pT stage. GATA3 immunostaining results for both antibodies were not associated with overall survival in 586 patients treated by cystectomy for pT2-4 urothelial carcinoma. The results of our study identify GATA3 expression as a frequent event in noninvasive urothelial carcinomas with favorable tumor features. Loss of GATA3 immunostaining is linked with muscle-invasive disease but is largely unrelated to pathological parameters and patient prognosis.
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Affiliation(s)
- Henning Plage
- Department of Urology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, 10117 Berlin, Germany
| | - Henrik Samtleben
- Department of Pathology, Academic Hospital Fuerth, 90766 Fuerth, Germany
| | - Sebastian Hofbauer
- Department of Urology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, 10117 Berlin, Germany
| | - Kira Kornienko
- Department of Urology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, 10117 Berlin, Germany
| | - Sarah Weinberger
- Department of Urology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, 10117 Berlin, Germany
| | - Paul Giacomo Bruch
- Department of Urology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, 10117 Berlin, Germany
| | - Sefer Elezkurtaj
- Institute of Pathology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, 10117 Berlin, Germany
| | - Florian Roßner
- Institute of Pathology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, 10117 Berlin, Germany
| | - Simon Schallenberg
- Institute of Pathology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, 10117 Berlin, Germany
| | - Martina Kluth
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Maximilian Lennartz
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Niclas C Blessin
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Andreas H Marx
- Department of Pathology, Academic Hospital Fuerth, 90766 Fuerth, Germany
| | - Margit Fisch
- Department of Urology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Michael Rink
- Department of Urology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Marcin Slojewski
- Department of Urology and Urological Oncology, Pomeranian Medical University, 70-204 Szczeci, Poland
| | - Krystian Kaczmarek
- Department of Urology and Urological Oncology, Pomeranian Medical University, 70-204 Szczeci, Poland
| | - Thorsten Ecke
- Department of Urology, Helios Hospital Bad Saarow, 15526 Bad Saarow, Germany
| | - Steffen Hallmann
- Department of Urology, Helios Hospital Bad Saarow, 15526 Bad Saarow, Germany
| | - Stefan Koch
- Department of Pathology, Helios Hospital Bad Saarow, 15526 Bad Saarow, Germany
| | - Nico Adamini
- Department of Urology, Albertinen Hospital, 22457 Hamburg, Germany
| | - Sarah Minner
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Ronald Simon
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
| | - Guido Sauter
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Tobias Klatte
- Department of Urology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, 10117 Berlin, Germany
| | - Thorsten Schlomm
- Department of Urology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, 10117 Berlin, Germany
| | - David Horst
- Institute of Pathology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, 10117 Berlin, Germany
| | - Henrik Zecha
- Department of Urology, Albertinen Hospital, 22457 Hamburg, Germany
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Kafkasli A, Yazici O, Can U, Dinçer E, Akça O, Canguven O. Testosterone status is not associated with bladder cancer parameters in adult male patients: results of a prospective controlled study. Aging Male 2021; 24:101-105. [PMID: 34338109 DOI: 10.1080/13685538.2020.1808968] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
Abstract
PURPOSE This controlled study assessed whether there was a correlation between serum total testosterone levels and bladder cancer (BCa) in terms of tumor grade and stage as objective measures in adult men. MATERIALS AND METHOD Our prospectively-designed study included 257 patients who were diagnosed with primary BCa and its surgery between January 2017 and January 2020. Hundred and forty patients who had surgery in the same period with TUR for prostate or endoscopic ureteral stone treatment were included in the study as a control group. All patients in the study and control groups were male. The age range of the patients was between 34 and 90 years old. In order to examine groups, fasting blood glucose, lipid profile, albumin, total testosterone, and vitamin D levels of all patients included in the study. RESULTS The relationship between tumor aggression and total testosterone level was investigated with a multinomial logistic regression model, where the control group was accepted as a reference, following adjustment for potential confounding variables, including age and serum albumin levels. Testosterone level was not found to be associated with any of the categories that determine tumor aggressiveness (p > 0.05). CONCLUSION In the present study, there was no correlation between any categories that determine tumor aggressiveness of BCa and total testosterone levels in adult men. It is obvious that our findings should be supported and further investigations are needed.
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Affiliation(s)
- Alper Kafkasli
- Dr Lütfi Kırdar Kartal Eğitim ve Araştırma Hastanesi, Istanbul, Turkey
| | - Ozgur Yazici
- Department of Urology, Haseki Training and Research Hospital, Istanbul, Turkey
| | - Utku Can
- Dr Lütfi Kırdar Kartal Eğitim ve Araştırma Hastanesi, Istanbul, Turkey
| | - Erdinç Dinçer
- Dr Lütfi Kırdar Kartal Eğitim ve Araştırma Hastanesi, Istanbul, Turkey
| | - Oktay Akça
- Dr Lütfi Kırdar Kartal Eğitim ve Araştırma Hastanesi, Istanbul, Turkey
| | - Onder Canguven
- Hamad General Hospital, Doha, Qatar
- Weill Cornell Medicine, Urology, New York, NY, USA
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Fan B, Mohammed A, Huang Y, Luo H, Zhang H, Tao S, Xu W, Liu Q, He T, Jin H, Sun M, Sun M, Yun Z, Zhao R, Wu G, Li X. Can Aspirin Use Be Associated With the Risk or Prognosis of Bladder Cancer? A Case-Control Study and Meta-analytic Assessment. Front Oncol 2021; 11:633462. [PMID: 34350107 PMCID: PMC8327774 DOI: 10.3389/fonc.2021.633462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Accepted: 06/30/2021] [Indexed: 12/03/2022] Open
Abstract
Aspirin, widely used to prevent cardiovascular disease, had been linked to the incidence of bladder cancer (BCa). Existing studies focusing on Chinese populations are relatively rare, especially for Northeast China. Meanwhile, relevant studies on the effects of aspirin on the occurrence or prognosis of BCa are inconsistent or even controversial. First, in the case control study, logistic regression analysis was used to investigate the association between aspirin intake and risk of BCa including 1121 patients with BCa and the 2242 controls. Subsequently, Kaplan-Meier curve and Cox regression analyses were applied to explore the association between aspirin intake and clinicopathological factors which may predict overall survival (OS) and recurrence-free survival (RFS) of BCa patients. Finally, we quantificationally combined the results with those from the published literature evaluating aspirin intake and its effects on the occurrence, outcome of surgery and prognosis of BCa by meta-analysis up to May 1, 2021.Our case-control study demonstrated that the regular use of aspirin was not associated with a reduced incidence of BCa (P=0.175). Stratified analyses of sex showed that aspirin intake did not lead to a lower risk of BCa in female patients (P=0.063). However, the male population who regularly took aspirin had a lower incidence of BCa (OR=0.748, 95% CI= 0.584-0.958, P=0.021). Subgroup analyses stratified by smoking found a significant reduction in the risk of BCa in current smokers with aspirin intake (OR=0.522, 95% CI=0.342-0.797, P=0.002). In terms of prognosis of BCa, patients with a history of aspirin intake did not had a markedly longer OS or RFS than those with no history of aspirin intake by Kaplan-Meier curves. Stratified analysis by sex showed no correlation between aspirin intake and the recurrence or survival of BCa for either male or female patients. However, in people younger than 68, aspirin intake seemed to have prolonged effects for overall survival (HR=3.876; 95% CI=1.326-11.325, P=0.019). Then, we performed a meta-analysis and the combined results from 19 articles and our study involving more than 39524 BCa cases indicated that aspirin intake was not associated with the occurrence of BCa (P=0.671). Subgroup analysis by whether regular use of aspirin, by the mean duration of use of aspirin, by sex, by smoking exposure, by research region and by study type also supported the above results. In terms of the impact of aspirin intake on the prognosis of patients with BCa, 11 articles and our study involving 8825 BCa cases were eligible. The combined results showed that patients with aspirin intake did not have significantly influence on survival, recurrence, progression and metastasis than those without aspirin intake. On the whole, both our retrospective study and literature meta-analysis suggested a lack of a strong relevant association between the use of aspirin and the incidence or prognosis of BCa. Thus, additional long-term follow-up prospective research is warranted to clarify the association of aspirin with BCa incidence and prognosis.
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Affiliation(s)
- Bo Fan
- Department of Urology, Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Alradhi Mohammed
- Department of Urology, Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Yuanbin Huang
- Department of Urology, Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Hong Luo
- Clinical Medicine, Dalian Medical University, Dalian, China
| | - Hongxian Zhang
- Department of Urology, Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Shenghua Tao
- Department of Urology, Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Weijiao Xu
- Clinical Medicine, Dalian Medical University, Dalian, China
| | - Qian Liu
- Medical Imaging, Dalian Medical University, Dalian, China
| | - Tao He
- Department of Urology, Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Huidan Jin
- Department of Anaesthesiology, Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, China
| | - Mengfan Sun
- Department of Pharmacy, Zhongshan College of Dalian Medical University, Dalian, China
| | - Man Sun
- Clinical Medicine, Dalian Medical University, Dalian, China
| | - Zhifei Yun
- Clinical Medicine, Dalian Medical University, Dalian, China
| | - Rui Zhao
- Department of Pharmacy, Zhongshan College of Dalian Medical University, Dalian, China
| | - Guoyu Wu
- Department of Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Xiancheng Li
- Department of Urology, Second Affiliated Hospital of Dalian Medical University, Dalian, China
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High Androgen Receptor mRNA Expression Is Associated with Improved Outcome in Patients with High-Risk Non-Muscle-Invasive Bladder Cancer. Life (Basel) 2021; 11:life11070642. [PMID: 34209360 PMCID: PMC8306811 DOI: 10.3390/life11070642] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 06/24/2021] [Accepted: 06/28/2021] [Indexed: 12/21/2022] Open
Abstract
The role of the androgen receptor (AR) in non-muscle-invasive bladder cancer (NMIBC) remains controversial. We retrospectively analyzed the mRNA expression of AR using RT-qPCR in 95 patients with high-risk NMIBC treated with a bladder-sparing approach and correlated AR with clinical data and recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS). The mRNA expression of AR and KRT5, i.e., the basal-like subtype, was strongly correlated (rs = 0.456; p < 0.001). AR (p = 0.053) and KRT5 (p = 0.029) mRNA expression was negatively correlated with tumor grade. Kaplan–Meier analyses indicated significantly prolonged CSS (p = 0.020) and OS (p = 0.015) and a trend towards longer RFS (p = 0.051) in patients with high AR expression. High KRT5 expression was associated with significantly longer RFS (p = 0.033), CSS (p = 0.029) and OS (p = 0.030), while high KRT20 expression was associated with reduced RFS (p = 0.042). In multivariable analysis, none of the molecular markers was an independent prognostic factor. When performing a substratification with regard to molecular markers and clinicopathological parameters, high AR expression showed improved OS in patients with high KRT20 mRNA expression (p = 0.041). Women showed significantly longer OS in cases with high AR expression (p = 0.011). High AR was associated with significantly improved CSS in males (p = 0.044) and patients with instillation therapy (p = 0.040), while OS was improved regardless of instillation therapy. Younger patients with high AR expression had significantly improved RFS (p = 0.021), CSS (p = 0.014) and OS (p = 0.007). RFS was also improved in patients with high AR and low expression of either KRT5 (p = 0.003) or KRT20 (p = 0.014), but not in patients with high expression of KRT5 or KRT20. In conclusion, high AR mRNA expression is correlated with KRT5 mRNA expression and is associated with an improved outcome in high-risk NMIBC.
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10
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Luna-Velez MV, Dijkstra JJ, Heuschkel MA, Smit FP, van de Zande G, Smeets D, Sedelaar JPM, Vermeulen M, Verhaegh GW, Schalken JA. Androgen receptor signalling confers clonogenic and migratory advantages in urothelial cell carcinoma of the bladder. Mol Oncol 2021; 15:1882-1900. [PMID: 33797847 PMCID: PMC8253097 DOI: 10.1002/1878-0261.12957] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 03/31/2021] [Indexed: 12/24/2022] Open
Abstract
Bladder urothelial cell carcinoma (UCC) incidence is about three times higher in men compared with women. There are several indications for the involvement of hormonal factors in the aetiology of UCC. Here, we provide evidence of androgen signalling in UCC progression. Microarray and qPCR analysis revealed that the androgen receptor (AR) mRNA level is upregulated in a subset of UCC cases. In an AR‐positive UCC‐derived cell line model, UM‐UC‐3‐AR, androgen treatment increased clonogenic capacity inducing the formation of big stem cell‐like holoclones, while AR knockdown or treatment with the AR antagonist enzalutamide abrogated this clonogenic advantage. Additionally, blockage of AR signalling reduced the cell migration potential of androgen‐stimulated UM‐UC‐3‐AR cells. These phenotypic changes were accompanied by a rewiring of the transcriptome with almost 300 genes being differentially regulated by androgens, some of which correlated with AR expression in UCC patients in two independent data sets. Our results demonstrate that AR signals in UCC favouring the development of an aggressive phenotype and highlights its potential as a therapeutic target for bladder cancer.
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Affiliation(s)
- Maria V Luna-Velez
- Department of Urology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.,Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Oncode Institute, Radboud University, Nijmegen, the Netherlands
| | - Jelmer J Dijkstra
- Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Oncode Institute, Radboud University, Nijmegen, the Netherlands
| | - Marina A Heuschkel
- Department of Urology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands
| | | | - Guillaume van de Zande
- Department of Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Dominique Smeets
- Department of Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands
| | - J P Michiel Sedelaar
- Department of Urology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Michiel Vermeulen
- Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Oncode Institute, Radboud University, Nijmegen, the Netherlands
| | - Gerald W Verhaegh
- Department of Urology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Jack A Schalken
- Department of Urology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands
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11
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Abd Raboh NM, Hakim SA, Abd El Atti RM. Implications of androgen receptor and FUS expression on tumor progression in urothelial carcinoma. Histol Histopathol 2020; 36:325-337. [PMID: 33354760 DOI: 10.14670/hh-18-295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Androgen receptor (AR) interact with many pathways involved in bladder cancer development and progression. FUS (fused in liposarcoma), a multifunctional protein essential for different cellular processes, has been demonstrated as a key link between androgen receptor signaling and cell-cycle progression in prostate cancer but has not been examined in urothelial carcinoma (UC) despite an intimate association between prostate and bladder carcinogenesis. AIM To examine the immunohistochemical expression of AR and FUS in urothelial carcinoma in relation to prognostic parameters and to extrapolate any possible link between the expression of both markers and tumor progression. STUDY DESIGN Retrospective study using immunohistochemical staining for AR and FUS on (88) cases of urothelial carcinoma. RESULTS AR shows statistically significant relations with late tumor stage, high tumor grade, and non-papillary tumor pattern. On the other hand, FUS expression correlates with early tumor stage, low tumor grade and papillary pattern. An inverse relation is found between AR and FUS expression (p=0.001). Cases with high AR IHC expression show statistically significant shorter OS, RFS and PFS compared to cases with low AR expression. Cases with high FUS IHC expression reveal statistically significant longer OS, RFS and PFS compared to cases with low FUS expression. CONCLUSION FUS expression is associated with favorable prognostic parameters of UC. A possible interaction is suggested between FUS and AR pathways involved in urothelial cancer progression. Manipulating FUS levels and androgen deprivation therapy can provide new promising targets for treatment trials.
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Affiliation(s)
| | - Sarah Adel Hakim
- Department of Pathology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
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12
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Kim A, Kim MS, Ahn JH, Choi WS, Park HK, Kim HG, Paick SH. Clinical significance of 5-α reductase inhibitor and androgen deprivation therapy in bladder cancer incidence, recurrence, and survival: a meta-analysis and systemic review. Aging Male 2020; 23:971-978. [PMID: 31724468 DOI: 10.1080/13685538.2019.1646238] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/25/2022] Open
Abstract
PURPOSE This study aimed to investigate the effect of androgen suppression therapy (AST), comprising a 5-α reductase inhibitor (5-ARi) and androgen deprivation therapy (ADT), on the risk of bladder cancer incidence, recurrence, and mortality. MATERIALS AND METHODS We used the PRISMA statement to report the methods and results of this meta-analysis. Bladder cancer incidence, recurrence, and mortality after 5-ARi treatment and ADT were assessed using risk ratios (RRs) and hazard ratios (HRs) with 95% confidence intervals (CIs). The protocol of this study is registered in the PROSPERO database (No. CRD42018118627). RESULTS We analyzed nine studies (n = 377,427) assessing the secondary effect of AST, with a mean follow-up period of 6 years (range, 2-13 years). Our result showed that the incidence of bladder cancer was significantly reduced when 5-ARi treatment (RR, 0.69; 95% CI, 0.58-0.81; I2 =0%) and ADT (HR, 0.81; 95% CI, 0.70-0.94; I2 =33%) were initiated before diagnosing bladder cancer. When treatment was initiated after diagnosing bladder cancer, 5-ARi treatment reduced cancer-specific mortality (RR, 0.29; 95% CI, 0.20-0.42; I2 =4.1%), whereas ADT reduced bladder cancer recurrence (HR, 0.30; 95% CI, 0.19-0.49; I2 =0%). CONCLUSIONS This study corroborates that the use of 5-ARi and ADT could be helpful in managing bladder cancer and should not be limited to prostatic abnormalities.
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Affiliation(s)
- Aram Kim
- Department of Urology, Konkuk University Medical Center, Konkuk University School, of Medicine, Seoul, Korea
| | - Min Seo Kim
- College of Medicine, Korea University, Seoul, Korea
| | - Jae-Hak Ahn
- Department of Urology, Konkuk University Medical Center, Konkuk University School, of Medicine, Seoul, Korea
| | - Woo Suk Choi
- Department of Urology, Konkuk University Medical Center, Konkuk University School, of Medicine, Seoul, Korea
| | - Hyoung Keun Park
- Department of Urology, Konkuk University Medical Center, Konkuk University School, of Medicine, Seoul, Korea
| | - Hyeong Gon Kim
- Department of Urology, Konkuk University Medical Center, Konkuk University School, of Medicine, Seoul, Korea
| | - Sung Hyun Paick
- Department of Urology, Konkuk University Medical Center, Konkuk University School, of Medicine, Seoul, Korea
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13
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Soleymani Fard S, Yazdanbod M, Sotoudeh M, Bashash D, Mahmoodzadeh H, Saliminejad K, Mousavi SA, Ghaffari SH, Alimoghaddam K. Prognostic and Therapeutic Significance of Androgen Receptor in Patients with Gastric Cancer. Onco Targets Ther 2020; 13:9821-9837. [PMID: 33061460 PMCID: PMC7537849 DOI: 10.2147/ott.s265364] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Accepted: 08/29/2020] [Indexed: 01/02/2023] Open
Abstract
Purpose The clinical studies carried out in the last few decades unequivocally introduced activated androgen receptor (AR) as a pathogenic feature of human malignancies which not only endows cancer cells with survival advantage, but also may be exploited for anticancer interventions. Patients and Methods In this study, we have investigated the expression profile of AR and EMT-related genes in fresh gastric cancer (GC), adjacent nontumor and normal gastric tissues, as well as the effect and molecular mechanisms of AR inhibition in GC cell lines. Results Amongst 60 GC patients, 66.7% overexpressed AR that was remarkably correlated with the overexpression of Snail, β-catenin, Twist1, and STAT3. AR overexpression was also remarkably associated with unfavorable outcome (HR=3.478, P=0.001); however, multivariate Cox regression analysis indicated that it was not an independent prognostic factor (HR=2.089, P=0.056). This study has investigated simultaneous assessment of AR and EMT-related genes expression and indicated that concurrent overexpression of AR and Snail is an independent unfavorable factor for GC overall survival after adjustment with other variables (HR=2.382, P=0.021). Interestingly, the inhibition of AR signaling by potent AR antagonist enzalutamide suppressed cell growth, migration and invasion of GC cells via regulation of apoptosis-, cell cycle-, and EMT-related gene expressions. Conclusion Our findings have clinical importance proposing AR as an important prognostic factor involved in GC progression and metastasis, and submit AR inhibition as an appealing therapeutic approach for GC patients, either as a single agent or in a combined-modal strategy.
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Affiliation(s)
- Shahrzad Soleymani Fard
- Hematology, Oncology and Stem Cell Transplantation Research Institute, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Masoud Sotoudeh
- Digestive Oncology Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Davood Bashash
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Habibollah Mahmoodzadeh
- Department of Surgical Oncology, Cancer Institute, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Kioomars Saliminejad
- Hematology, Oncology and Stem Cell Transplantation Research Institute, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed Asadollah Mousavi
- Hematology, Oncology and Stem Cell Transplantation Research Institute, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed H Ghaffari
- Hematology, Oncology and Stem Cell Transplantation Research Institute, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Kamran Alimoghaddam
- Hematology, Oncology and Stem Cell Transplantation Research Institute, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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Lee KH, Kim BC, Jeong SH, Jeong CW, Ku JH, Kwak C, Kim HH. Histone Demethylase LSD1 Regulates Kidney Cancer Progression by Modulating Androgen Receptor Activity. Int J Mol Sci 2020; 21:6089. [PMID: 32847068 PMCID: PMC7503698 DOI: 10.3390/ijms21176089] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 08/13/2020] [Accepted: 08/19/2020] [Indexed: 02/06/2023] Open
Abstract
Kidney cancer is one of the most difficult cancers to treat by targeted and radiation therapy. Therefore, identifying key regulators in this cancer is especially important for finding new drugs. We focused on androgen receptor (AR) regulation by its epigenetic co-regulator lysine-specific histone demethylase 1 (LSD1) in kidney cancer development. LSD1 knock-down in kidney cancer cells decreased expression of AR target genes. Moreover, the binding of AR to target gene promoters was reduced and histone methylation status was changed in LSD1 knock-down kidney cancer cells. LSD1 knock-down also slowed growth and decreased the migration ability of kidney cancer cells. We found that pargyline, known as a LSD1 inhibitor, can reduce AR activity in kidney cancer cells. The treatment of kidney cancer cells with pargyline delayed growth and repressed epithelial-mesenchymal transition (EMT) markers. These effects were additively enhanced by co-treatment with the AR inhibitor enzalutamide. Down-regulation of LSD1 in renal cancer cells (RCC) attenuated in vivo tumor growth in a xenograft mouse model. These results provide evidence that LSD1 can regulate kidney cancer cell growth via epigenetic control of AR transcription factors and that LSD1 inhibitors may be good candidate drugs for treating kidney cancer.
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MESH Headings
- Animals
- Carcinoma, Renal Cell/genetics
- Carcinoma, Renal Cell/metabolism
- Carcinoma, Renal Cell/pathology
- Cell Line, Tumor
- Cells, Cultured
- Disease Progression
- Gene Expression Regulation, Neoplastic
- HEK293 Cells
- Histone Demethylases/genetics
- Histone Demethylases/physiology
- Humans
- Kidney Neoplasms/genetics
- Kidney Neoplasms/metabolism
- Kidney Neoplasms/pathology
- Male
- Mice
- Mice, Inbred NOD
- Mice, SCID
- Receptors, Androgen/genetics
- Receptors, Androgen/metabolism
- Signal Transduction/genetics
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Affiliation(s)
- Kyoung-Hwa Lee
- Department of Urology, Seoul National University Hospital, Seoul 03080, Korea; (K.-H.L.); (B.-C.K.); (C.W.J.); (J.H.K.)
| | - Byung-Chan Kim
- Department of Urology, Seoul National University Hospital, Seoul 03080, Korea; (K.-H.L.); (B.-C.K.); (C.W.J.); (J.H.K.)
| | - Seung-Hwan Jeong
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34052, Korea;
| | - Chang Wook Jeong
- Department of Urology, Seoul National University Hospital, Seoul 03080, Korea; (K.-H.L.); (B.-C.K.); (C.W.J.); (J.H.K.)
| | - Ja Hyeon Ku
- Department of Urology, Seoul National University Hospital, Seoul 03080, Korea; (K.-H.L.); (B.-C.K.); (C.W.J.); (J.H.K.)
| | - Cheol Kwak
- Department of Urology, Seoul National University Hospital, Seoul 03080, Korea; (K.-H.L.); (B.-C.K.); (C.W.J.); (J.H.K.)
- Department of Urology, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Hyeon Hoe Kim
- Department of Urology, Seoul National University Hospital, Seoul 03080, Korea; (K.-H.L.); (B.-C.K.); (C.W.J.); (J.H.K.)
- Department of Urology, Seoul National University College of Medicine, Seoul 03080, Korea
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15
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Lee KH, Kim BC, Jeong SH, Jeong CW, Ku JH, Kim HH, Kwak C. Histone Demethylase KDM7A Regulates Androgen Receptor Activity, and Its Chemical Inhibitor TC-E 5002 Overcomes Cisplatin-Resistance in Bladder Cancer Cells. Int J Mol Sci 2020; 21:5658. [PMID: 32781788 PMCID: PMC7460860 DOI: 10.3390/ijms21165658] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 08/04/2020] [Accepted: 08/04/2020] [Indexed: 12/11/2022] Open
Abstract
Histone demethylase KDM7A regulates many biological processes, including differentiation, development, and the growth of several cancer cells. Here, we have focused on the role of KDM7A in bladder cancer cells, especially under drug-resistant conditions. When the KDM7A gene was knocked down, bladder cancer cell lines showed impaired cell growth, increased cell death, and reduced rates of cell migration. Biochemical studies revealed that KDM7A knockdown in the bladder cancer cells repressed the activity of androgen receptor (AR) through epigenetic regulation. When we developed a cisplatin-resistant bladder cancer cell line, we found that AR expression was highly elevated. Upon treatment with TC-E 5002, a chemical inhibitor of KDM7A, the cisplatin-resistant bladder cancer cells, showed decreased cell proliferation. In the mouse xenograft model, KDM7A knockdown or treatment with its inhibitor reduced the growth of the bladder tumor. We also observed the upregulation of KDM7A expression in patients with bladder cancer. The findings suggest that histone demethylase KDM7A mediates the growth of bladder cancer. Moreover, our findings highlight the therapeutic potential of the KMD7A inhibitor, TC-E 5002, in patients with cisplatin-resistant bladder cancer.
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MESH Headings
- Aged
- Aged, 80 and over
- Animals
- Apoptosis/drug effects
- Apoptosis/genetics
- Cell Line, Tumor
- Cell Movement/drug effects
- Cell Movement/genetics
- Cell Nucleus/drug effects
- Cell Nucleus/metabolism
- Cell Proliferation/drug effects
- Cell Proliferation/genetics
- Cisplatin/pharmacology
- Cisplatin/therapeutic use
- Drug Resistance, Neoplasm/drug effects
- Drug Resistance, Neoplasm/genetics
- Epigenesis, Genetic/drug effects
- Epithelial-Mesenchymal Transition/drug effects
- Epithelial-Mesenchymal Transition/genetics
- Female
- Gene Expression Regulation, Neoplastic/drug effects
- Humans
- Jumonji Domain-Containing Histone Demethylases/metabolism
- Male
- Methylation
- Mice, Inbred NOD
- Middle Aged
- Neoplasm Invasiveness
- Promoter Regions, Genetic/genetics
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Receptors, Androgen/genetics
- Receptors, Androgen/metabolism
- Transcription, Genetic/drug effects
- Tumor Burden/drug effects
- Up-Regulation/drug effects
- Up-Regulation/genetics
- Urinary Bladder Neoplasms/drug therapy
- Urinary Bladder Neoplasms/genetics
- Urinary Bladder Neoplasms/metabolism
- Urinary Bladder Neoplasms/pathology
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Kyoung-Hwa Lee
- Department of Urology, Seoul National University Hospital, Seoul 03080, Korea; (K.-H.L.); (B.-C.K.); (C.W.J.); (J.H.K.); (H.H.K.)
| | - Byung-Chan Kim
- Department of Urology, Seoul National University Hospital, Seoul 03080, Korea; (K.-H.L.); (B.-C.K.); (C.W.J.); (J.H.K.); (H.H.K.)
| | - Seung-Hwan Jeong
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34052, Korea;
| | - Chang Wook Jeong
- Department of Urology, Seoul National University Hospital, Seoul 03080, Korea; (K.-H.L.); (B.-C.K.); (C.W.J.); (J.H.K.); (H.H.K.)
| | - Ja Hyeon Ku
- Department of Urology, Seoul National University Hospital, Seoul 03080, Korea; (K.-H.L.); (B.-C.K.); (C.W.J.); (J.H.K.); (H.H.K.)
| | - Hyeon Hoe Kim
- Department of Urology, Seoul National University Hospital, Seoul 03080, Korea; (K.-H.L.); (B.-C.K.); (C.W.J.); (J.H.K.); (H.H.K.)
| | - Cheol Kwak
- Department of Urology, Seoul National University Hospital, Seoul 03080, Korea; (K.-H.L.); (B.-C.K.); (C.W.J.); (J.H.K.); (H.H.K.)
- Department of Urology, Seoul National University College of Medicine, Seoul 03080, Korea
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16
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Ikarashi N, Hoshino M, Ono T, Toda T, Yazawa Y, Sugiyama K. A Mechanism by which Ergosterol Inhibits the Promotion of Bladder Carcinogenesis in Rats. Biomedicines 2020; 8:biomedicines8070180. [PMID: 32605038 PMCID: PMC7400612 DOI: 10.3390/biomedicines8070180] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 06/24/2020] [Accepted: 06/25/2020] [Indexed: 11/25/2022] Open
Abstract
We previously showed that ergosterol has an inhibitory effect on bladder carcinogenesis. In this study, we aimed to elucidate the molecular mechanism by which ergosterol inhibits bladder carcinogenesis using a rat model of N-butyl-N-(4-hydroxybutyl)nitrosamine-induced bladder cancer. The messenger ribonucleic acid (mRNA) expression level of the cell cycle-related gene cyclin D1 and inflammation-related gene cyclooxygenase-2 in bladder epithelial cells was significantly increased in the carcinogenesis group compared with the control group. In contrast, in ergosterol-treated rats, these increases were significantly suppressed. Ergosterol did not affect the plasma testosterone concentration or the binding of dihydrotestosterone to androgen receptor (AR). The mRNA expression levels of 5α-reductase type 2 and AR were higher in the carcinogenesis group than in the control group but were significantly decreased by ergosterol administration. These results suggest that ergosterol inhibits bladder carcinogenesis by modulating various aspects of the cell cycle, inflammation-related signaling, and androgen signaling. Future clinical application of the preventive effect of ergosterol on bladder carcinogenesis is expected.
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Affiliation(s)
- Nobutomo Ikarashi
- Department of Biomolecular Pharmacology, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan
- Correspondence: (N.I.); (K.S.); Tel.: +81-3-5498-5918 (N.I.)
| | - Motohiro Hoshino
- Department of Clinical Pharmacokinetics, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan; (M.H.); (T.O.)
| | - Tetsuya Ono
- Department of Clinical Pharmacokinetics, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan; (M.H.); (T.O.)
| | - Takahiro Toda
- Division of Pharmacology, Faculty of Pharmaceutical Sciences, Teikyo Heisei University, 4-21-2 Nakano, Nakano-ku, Tokyo 164-8530, Japan;
| | - Yasuharu Yazawa
- Department of Clinical Pharmaceutics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan;
| | - Kiyoshi Sugiyama
- Department of Functional Molecular Kinetics, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan
- Correspondence: (N.I.); (K.S.); Tel.: +81-3-5498-5918 (N.I.)
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17
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Inhibitory effect of ergosterol on bladder carcinogenesis is due to androgen signaling inhibition by brassicasterol, a metabolite of ergosterol. J Nat Med 2020; 74:680-688. [PMID: 32488609 DOI: 10.1007/s11418-020-01419-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Accepted: 05/24/2020] [Indexed: 10/24/2022]
Abstract
We previously revealed that Choreito, a traditional Kampo medicine, strongly inhibits bladder carcinogenesis promotion. We have also shown that Polyporus sclerotium, which is one of the crude drugs in Choreito, has the strongest bladder carcinogenesis inhibitory effect and that the ergosterol contained in Polyporus sclerotium is the main active component. In this study, we analyzed the mechanism by which ergosterol inhibits bladder carcinogenesis. Rats were given an N-butyl-N-(4-hydroxybutyl) nitrosamine (BHBN) solution ad libitum, and then a promoter [saccharin sodium (SS), DL-tryptophan, or BHBN] was administered together with ergosterol or its metabolite, brassicasterol. The bladders were removed from rats, and the inhibitory effect on carcinogenesis promotion was evaluated by an agglutination assay with concanavalin A (Con A). Although the oral administration of ergosterol inhibited the promotion of bladder carcinogenesis with SS, the intraperitoneal administration of brassicasterol showed a stronger effect. The effect of brassicasterol on carcinogenesis promotion was observed regardless of the type of promoter. Administration of testosterone to castrated rats increased the number of cell aggregates caused by Con A. In contrast, intraperitoneal administration of brassicasterol to castrated rats treated with testosterone significantly decreased the number of cell aggregates, confirming the inhibition of bladder carcinogenesis promotion. The inhibitory effect of ergosterol on bladder carcinogenesis is due to brassicasterol, a metabolite of ergosterol. The action of brassicasterol via androgen signaling may play a role in the inhibitory effect on bladder carcinogenesis promotion.
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18
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Rubin JB, Lagas JS, Broestl L, Sponagel J, Rockwell N, Rhee G, Rosen SF, Chen S, Klein RS, Imoukhuede P, Luo J. Sex differences in cancer mechanisms. Biol Sex Differ 2020; 11:17. [PMID: 32295632 PMCID: PMC7161126 DOI: 10.1186/s13293-020-00291-x] [Citation(s) in RCA: 178] [Impact Index Per Article: 35.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2019] [Accepted: 03/18/2020] [Indexed: 02/07/2023] Open
Abstract
We now know that cancer is many different diseases, with great variation even within a single histological subtype. With the current emphasis on developing personalized approaches to cancer treatment, it is astonishing that we have not yet systematically incorporated the biology of sex differences into our paradigms for laboratory and clinical cancer research. While some sex differences in cancer arise through the actions of circulating sex hormones, other sex differences are independent of estrogen, testosterone, or progesterone levels. Instead, these differences are the result of sexual differentiation, a process that involves genetic and epigenetic mechanisms, in addition to acute sex hormone actions. Sexual differentiation begins with fertilization and continues beyond menopause. It affects virtually every body system, resulting in marked sex differences in such areas as growth, lifespan, metabolism, and immunity, all of which can impact on cancer progression, treatment response, and survival. These organismal level differences have correlates at the cellular level, and thus, males and females can fundamentally differ in their protections and vulnerabilities to cancer, from cellular transformation through all stages of progression, spread, and response to treatment. Our goal in this review is to cover some of the robust sex differences that exist in core cancer pathways and to make the case for inclusion of sex as a biological variable in all laboratory and clinical cancer research. We finish with a discussion of lab- and clinic-based experimental design that should be used when testing whether sex matters and the appropriate statistical models to apply in data analysis for rigorous evaluations of potential sex effects. It is our goal to facilitate the evaluation of sex differences in cancer in order to improve outcomes for all patients.
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Affiliation(s)
- Joshua B Rubin
- Department of Pediatrics, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO, 63110, USA.
- Department of Neuroscience, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO, 63110, USA.
| | - Joseph S Lagas
- Department of Pediatrics, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO, 63110, USA
| | - Lauren Broestl
- Department of Pediatrics, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO, 63110, USA
| | - Jasmin Sponagel
- Department of Pediatrics, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO, 63110, USA
| | - Nathan Rockwell
- Department of Pediatrics, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO, 63110, USA
| | - Gina Rhee
- Department of Pediatrics, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO, 63110, USA
| | - Sarah F Rosen
- Department of Medicine, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO, 63110, USA
| | - Si Chen
- Department of Biomedical Engineering, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO, 63110, USA
| | - Robyn S Klein
- Department of Neuroscience, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO, 63110, USA
- Department of Medicine, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO, 63110, USA
| | - Princess Imoukhuede
- Department of Biomedical Engineering, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO, 63110, USA
| | - Jingqin Luo
- Department of Surgery, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO, 63110, USA
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19
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Abstract
Men are at a higher risk of developing bladder cancer, but women present with more advanced disease and have more unfavourable outcomes. Although epidemiologic and genetical studies have underlined the multifactorial aetiology and gender-related differences of bladder cancer, there is lack of evidence-based recommendation for gender-specific management of bladder cancer. We summarize the evidence and most recent findings on gender-specific differences in bladder cancer incidence, diagnosis, treatment and outcome, spotlighting the gender disparities in genetic and hormonal risk factors, pelvic anatomy, diagnostic setting and surgical choices. We reviewed the literature published on PubMed between 1981 and 2018. Males have a threefold to fourfold higher risk of bladder cancer as compared to females; however, women have higher stage-for-stage mortality, being diagnosed with more advanced disease, mostly due to a delay in haematuria evaluation. Numerous studies indicate an increased risk of disease recurrence or progression in women with non-muscle-invasive bladder cancer treated with trans-urethral resection, with or without intravesical chemotherapy or immunotherapy, compared to males. In particular, recent molecular evidence show that there is an excess of female Ta mutant tumours. At the time of radical cystectomy, women have a significantly longer length of hospital stay, operative time, higher blood loss and higher 90-day mortality and perioperative complication rate. Moreover, females are less likely to receive a continent diversion. Future research should guarantee greater inclusion of women in trials and focus on improving the effectiveness of therapies in women, perhaps exploring different therapeutic approaches in men and women. Specific data on functional and oncological outcomes can be analysed to define predictive factors able to guide the surgeon in decisions based on evidence. It is urgently needed to limit gender-related discrepancies in early diagnosis and treatment of bladder cancer. Public awareness and bladder cancer female patients' consciousness on gender inequalities must be similarly uprisen.
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Affiliation(s)
- Mariangela Mancini
- Urological Clinic, Department of Surgical, Oncological and Gastroenterological Sciences and School of Medicine and Surgery, University of Padova, Padova, Italy
| | - Marialaura Righetto
- Urological Clinic, Department of Surgical, Oncological and Gastroenterological Sciences and School of Medicine and Surgery, University of Padova, Padova, Italy
| | - Giovannella Baggio
- Department of Medicine (DIMED) and School of Medicine and Surgery, University of Padova, Padova, Italy
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20
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Pastore AL, Fuschi A, DE Nunzio C, Balzarro M, Al Salhi Y, Velotti G, Martoccia A, Capone L, Amigoni N, Falsaperla M, Mattia C, Artibani W, Tubaro A, Carbone A. Possible role of 5-alpha reductase inhibitors in non-invasive bladder urothelial neoplasm: multicenter study. Minerva Urol Nephrol 2019; 74:337-343. [PMID: 31833718 DOI: 10.23736/s2724-6051.19.03563-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
BACKGROUND About 75% of urothelial bladder cancers are non-muscle invasive (NMIBC), and limited to mucosa (Ta or CIS) or sub-mucosa (T1). An increase of androgen expression and androgen receptors has a positive effect on oncogenic expression. We aimed to evaluate whether 5-alpha reductase inhibitors (5-ARI) have a role in NMIBC. METHODS We retrospectively evaluated the clinical and pathological data of 423 patients with NMIBC who underwent transurethral bladder resection. We considered the number of resections, number of total recurrences, time of recurrences, and histopathology details. The population was classified into two groups: treated and untreated with 5-ARIs. The enrolled patients were in treatment with 5ARIs for symptomatic prostatic hyperplasia for at least 12 months. Mean follow-up time was 30.43 months. RESULTS Patients treated with 5-ARIs had a lower rate of recurrence (14%) than the untreated group (37%). There was a significant difference in the mean number of recurrences between the untreated and the treated group (P=0.006). Furthermore, the treated group showed a significantly greater number of low than high grade tumors, compared to the untreated group (P≤0.05). There was a significant decrease in the number of muscle invasive tumors in treated patients (P=0.032). The recurrence-free survival rate of patients treated with 5-ARIs was significantly higher (P=0.0001). CONCLUSIONS Long-term treatment with 5-ARIs might reduce the risk of bladder tumor recurrence, extension of lesions and increase the recurrence-free survival rate. A long-term, randomized prospective study could definitively assess the possible role of these drugs.
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Affiliation(s)
- Antonio L Pastore
- Unit of Urology, Department of Medico-Surgical Sciences and Biotechnologies, Faculty of Pharmacy and Medicine, Sapienza University, Latina, Italy -
| | - Andrea Fuschi
- Unit of Urology, Department of Medico-Surgical Sciences and Biotechnologies, Faculty of Pharmacy and Medicine, Sapienza University, Latina, Italy
| | - Cosimo DE Nunzio
- Uroresearch Non-profit Association for Research in Urology, Latina, Italy
| | - Matteo Balzarro
- Department of Urology, Sant'Andrea Hospital, Sapienza University, Rome, Italy
| | - Yazan Al Salhi
- Unit of Urology, Department of Medico-Surgical Sciences and Biotechnologies, Faculty of Pharmacy and Medicine, Sapienza University, Latina, Italy
| | - Gennaro Velotti
- Unit of Urology, Department of Medico-Surgical Sciences and Biotechnologies, Faculty of Pharmacy and Medicine, Sapienza University, Latina, Italy
| | - Alessia Martoccia
- Unit of Urology, Department of Medico-Surgical Sciences and Biotechnologies, Faculty of Pharmacy and Medicine, Sapienza University, Latina, Italy
| | - Lorenzo Capone
- Unit of Urology, Department of Medico-Surgical Sciences and Biotechnologies, Faculty of Pharmacy and Medicine, Sapienza University, Latina, Italy
| | - Nelia Amigoni
- Department of Urology, Sant'Andrea Hospital, Sapienza University, Rome, Italy
| | - Mario Falsaperla
- Department of Urology, Verona University Hospital, University of Verona, Verona, Italy
| | - Consalvo Mattia
- Department of Urology, Vittorio Emanuele Hospital, Catania, Italy
| | - Walter Artibani
- Department of Urology, Sant'Andrea Hospital, Sapienza University, Rome, Italy
| | - Andrea Tubaro
- Uroresearch Non-profit Association for Research in Urology, Latina, Italy
| | - Antonio Carbone
- Unit of Urology, Department of Medico-Surgical Sciences and Biotechnologies, Faculty of Pharmacy and Medicine, Sapienza University, Latina, Italy
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21
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Xia N, Cui J, Zhu M, Xing R, Lu Y. Androgen receptor variant 12 promotes migration and invasion by regulating MYLK in gastric cancer. J Pathol 2019; 248:304-315. [PMID: 30737779 DOI: 10.1002/path.5257] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Revised: 01/14/2019] [Accepted: 02/06/2019] [Indexed: 12/30/2022]
Abstract
Androgen receptor (AR) and its variants (AR-Vs) promote tumorigenesis and metastasis in many hormone-related cancers, such as breast, prostate and hepatocellular cancers. However, the expression patterns and underlying molecular mechanisms of AR in gastric cancer (GC) are not fully understood. This study aimed to detect the expression of AR-Vs in GC and explored their role in metastasis of GC. Here, the AR expression form was identified in GC cell lines and tissues by RT-PCR and qPCR. Transwell assays and experimental lung metastasis animal models were used to assess the function of AR in cell migration and invasion. Downstream targets of AR were screened by bioinformatics, and identified by luciferase reporter assays and electrophoretic mobility shift assays. AR-v12 was identified as the main expression form in GC cell lines and tissues. Different from full length of AR, AR-v12 was localized to the nucleus independent of androgen. Upregulation of AR-v12 in primary GC tissues was significantly associated with metastasis. Overexpression of AR-v12 promoted migration and invasion independent of androgen. Knockdown of AR-v12 inhibited migration and invasion in vitro, as well as metastasis in vivo. Furthermore, AR-v12, serving as a transcription factor, promoted metastasis through regulating the promoter activity of MYLK. In AR-v12 overexpressing cells, knockdown of MYLK inhibited cell migration and invasion, while in AR-v12 knocked-down cells, overexpression of MYLK promoted cell migration and invasion. Collectively, our study demonstrates that AR-v12 is highly expressed in GC tissues and promotes migration and invasion through directly regulating MYLK. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Nan Xia
- Laboratory of Molecular Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, PR China
| | - Jiantao Cui
- Laboratory of Molecular Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, PR China
| | - Min Zhu
- Laboratory of Molecular Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, PR China
| | - Rui Xing
- Laboratory of Molecular Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, PR China
| | - Youyong Lu
- Laboratory of Molecular Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, PR China.,Department of Medical Oncology, Beijing Hospital, Beijing 100730, PR China
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22
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Yasui M, Kawahara T, Izumi K, Yao M, Ishiguro Y, Ishiguro H, Uemura H, Miyoshi Y. Androgen receptor mRNA expression is a predictor for recurrence-free survival in non-muscle invasive bladder cancer. BMC Cancer 2019; 19:331. [PMID: 30961575 PMCID: PMC6454612 DOI: 10.1186/s12885-019-5512-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2017] [Accepted: 03/25/2019] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND Non-muscular invasive bladder cancer (NMIBC) has a high risk of recurrence. As androgen receptor (AR) reportedly affects bladder cancer, we assessed the correlation between NMIBC recurrence and tumor AR expression in Japanese patients. METHODS We retrospectively reviewed 53 specimens of non-metastatic NMIBC, with recurrence-free survival (RFS) as the primary endpoint. We used real-time quantitative polymerase chain reaction to quantify AR mRNA expression. Kaplan-Meier product-limit estimators were used to assess RFS distribution, log-rank tests to analyze differences in RFS between high- and low-risk groups; and multivariate analyses of AR mRNA expression and other clinicopathological factors to predict independent factors for RFS. RESULTS The high AR mRNA-expressing group (n = 43) tended to have a longer median RFS (not reached) than did the low-AR group (n = 10; 9.04 months; P = 0.112). Multivariate analysis showed female sex (hazard ratio [HR]: 7.360, 95% CI: 1.649-32.856, P = 0.009), tumor size ≥3 cm (HR: 23.697, 95% CI: 4.383-128.117, P < 0.001) and low AR mRNA expression (HR: 0.202, 95% CI: 0.048-0.841, P = 0.028) to be independent predictors of shorter RFS. CONCLUSION Our study showed that low AR mRNA expression level is an independent risk factor for RFS in Japanese patients with NMIBC. Further studies are necessary but AR expression might be a new indicator of recurrence of NMIBC.
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Affiliation(s)
- Masato Yasui
- Department of Urology and Renal Transplantation, Yokohama City University Medical Center, 4-57 Urafune-cho, Minami-ku, Yokohama, 232-0024 Japan
| | - Takashi Kawahara
- Department of Urology and Renal Transplantation, Yokohama City University Medical Center, 4-57 Urafune-cho, Minami-ku, Yokohama, 232-0024 Japan
| | - Koji Izumi
- Department of Urology and Renal Transplantation, Yokohama City University Medical Center, 4-57 Urafune-cho, Minami-ku, Yokohama, 232-0024 Japan
| | - Masahiro Yao
- Department of Urology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Yukari Ishiguro
- Department of Urology and Renal Transplantation, Yokohama City University Medical Center, 4-57 Urafune-cho, Minami-ku, Yokohama, 232-0024 Japan
| | - Hitoshi Ishiguro
- Department of Urology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
- Photocatalyst Group, Special Research Laboratory, Kanagawa Academy of Science and Technology, Kawasaki, Japan
| | - Hiroji Uemura
- Department of Urology and Renal Transplantation, Yokohama City University Medical Center, 4-57 Urafune-cho, Minami-ku, Yokohama, 232-0024 Japan
| | - Yasuhide Miyoshi
- Department of Urology and Renal Transplantation, Yokohama City University Medical Center, 4-57 Urafune-cho, Minami-ku, Yokohama, 232-0024 Japan
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23
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Pretreatment Neutrophil to Lymphocyte Ratio (NLR) Predicts Prognosis for Castration Resistant Prostate Cancer Patients Underwent Enzalutamide. BIOMED RESEARCH INTERNATIONAL 2019; 2019:9450838. [PMID: 30800682 PMCID: PMC6360569 DOI: 10.1155/2019/9450838] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Revised: 11/26/2018] [Accepted: 12/11/2018] [Indexed: 12/29/2022]
Abstract
Introduction Nearly 80% of advanced prostate cancer patients respond to initial androgen deprivation therapy (ADT). However, ADT does not prevent the progression of prostate cancer over the long term, and the disease eventually progresses to castration-resistant prostate cancer (CRPC). Prior to the development of enzalutamide (ENZ) and abiraterone acetate, docetaxel was the only established treatment with life-prolongation for CRPC. ENZ is a second-generation anti-androgen receptor drug that has contributed to improving the prognosis of CRPC. Several studies have reported factors predicting the efficacy of ENZ; however, there are no confirmed biomarkers. The neutrophil-to-lymphocyte ratio (NLR) is an easily calculated biomarker that is associated with the prognosis of several solid malignancies. However, there were few studies investigated NLR for ENZ in patients with mCRPC. We examined the usefulness of the NLR as a predictive tool for ENZ. Methods We retrospectively examined a total of 106 CRPC patients who were treated with ENZ until September 2016 in Yokohama City University Hospital, Yokohama City University Medical Center, and National Cancer Center Hospital East. ENZ was routinely started as a dose of 160 mg per day; the dosage was reduced in some patients due to side effects. Drug holiday for 1-2 weeks or dose reduction to 80-120mg was done and no patients discontinued ENZ treatment due to adverse effects. ENZ was stopped when cancer progression was detected based on PSA elevation, radiographic findings, and deterioration of the patient's performance status. The cut-off NLRs for overall survival (OS) and cancer-specific survival (CSS) were determined based on the receiver-operator curves. Kaplan-Meier curves were used to analyze the factors associated with OS or CSS and a log-rank test was performed. A multivariate analysis was also performed to analyze the factors associated with the prognosis. Results We retrospectively reviewed 106 consecutive CRPC patients who were both treated with ENZ and were able to be counted before ENZ NLR. Cut-off point was 2.14 for both OS and CSS by receiver operator characteristic curve. The patients were then divided into the higher NLR group (≥2.14) and lower NLR group (<2.14). Multivariate analysis showed that NLR and predocetaxel chemotherapy were independent risk factors for both overall and cancer-specific survival. Conclusions The NLR might be a useful biomarker for predicting the prognosis of mCRPC patients who are treated with ENZ.
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24
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Yonekura S, Terauchi F, Hoshi K, Yamaguchi T, Kawai S. Androgen Receptor Predicts First and Multiple Recurrences in Non-Muscle Invasive Urothelial Carcinoma of the Bladder. Pathol Oncol Res 2018; 25:987-994. [PMID: 29862474 DOI: 10.1007/s12253-018-0431-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Accepted: 05/29/2018] [Indexed: 12/12/2022]
Abstract
The aim of this study is to investigate the role of androgen receptor (AR) expression on clinicopathologic characteristics, first recurrence free survival (RFS), progression free survival (PFS) and multiple recurrences in non-muscle invasive bladder cancer (NMIBC). AR expression in 40 paraffin-embedded specimens of primarily diagnosed NMIBC after transurethral resection was examined by immunohistochemistry using a monoclonal AR antibody. Associations between AR expression and clinicopathologic features and prognosis were statistically assessed. Multivariate Cox proportional hazards model was applied for evaluating predictive factors on RFS and PFS. For multiple recurrences, we used the Andersen-Gill model. AR was positive in 20/40 (50%) cases. Twenty-three patients (57.5%) had no recurrence, 10 (25.0%) had one recurrence, and 7 (17.5%) experienced more than one recurrence. AR expression and clinicopathologic features were not significantly correlated (P >0.05). Univariate analyses showed that AR expression was significantly associated with RFS and PFS (P <0.05). Via multivariate analyses, positive AR expression was significantly associated with lower risk of first recurrence (hazard ratio (HR) = 0.265; 95% confidence interval (95% CI) = 0.084-0.829; P = 0.022). Multivariate analysis of PFS was not feasible in our cohort. Using the multivariate Andersen-Gill model, positive AR expression in the primary tumor was an independent factor predicting lower risk of multiple recurrences (HR = 0.387, 95% CI = 0.161-0.927, P = 0.033). Androgen receptor expression is associated with first and multiple recurrences in NMIBC.
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Affiliation(s)
- Satoru Yonekura
- Department of Pathology, Tochigi Medical Center Shimotsuga Hospital, 420-1 Ohira-machi Kawatsure, Tochigi, Tochigi, 329-4498, Japan.
| | - Fumihito Terauchi
- Department of Urology, Tochigi Medical Center Shimotsuga Hospital, 420-1 Ohira-machi Kawatsure, Tochigi, Tochigi, 329-4498, Japan
| | - Kenji Hoshi
- Department of Pathology, Tochigi Medical Center Shimotsuga Hospital, 420-1 Ohira-machi Kawatsure, Tochigi, Tochigi, 329-4498, Japan
| | - Takehiko Yamaguchi
- Department of Pathology, Koshigaya Hospital, Dokkyo Medical University, 2-1-50 Minami-Koshigaya, Koshigaya, Saitama, 343-8555, Japan
| | - Shigeo Kawai
- Department of Pathology, Tochigi Medical Center Shimotsuga Hospital, 420-1 Ohira-machi Kawatsure, Tochigi, Tochigi, 329-4498, Japan
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25
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Wu S, Ye J, Wang Z, Lin SX, Lu M, Liang Y, Zhu X, Olumi AF, Zhong WD, Wu CL. Expression of aromatase in tumor related stroma is associated with human bladder cancer progression. Cancer Biol Ther 2018; 19:175-180. [PMID: 29303414 DOI: 10.1080/15384047.2017.1414762] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Putative gender differences in bladder cancer (BCa) have been proposed to result from sex hormone influence. Aromatase is the key enzyme catalyzing the conversion of androgens to estrogens which may result in an intratumoral microenviroment with increased estrogen production. In this study, we investigated the expression pattern of aromatase and its association with BCa progression. Tissue samples from 88 BCa patients who underwent cystectomy were obtained. Using immunohistochemistry (IHC), expression of aromatase in tumor epithelium (TE) and tumor related stroma (TS) were evaluated separately, and the association of aromatase expression status with pathologic variables and overall survival (OS) outcome was examined. High aromatase expression was found in 33/88 (37.5%) of TE and in 65/88 (73.9%) of TS. Increased aromatase expression in TE had a trend to correlate with male gender. Increased aromatase in TS was significantly associated with adverse pathologic variables including higher pathologic pT, positive lymph node metastasis (pN), lymphovascular invasion (LVI), and distant metastasis. In univariate analysis, high aromatase expression in TS was significantly associated with poorer overall survival (p = 0.014), but this association was not significant (p = 0.163) in multivariate cox analysis adjusted for independent factors including age at surgery and pN. These results demonstrate that aromatase expression in TS but not TE may play a critical role in BCa progression. Our findings provide direct evidence of aromatase involvement in BCa and suggest endocrine therapy may have a potential role in the treatment of BCa.
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Affiliation(s)
- Shulin Wu
- a Department of Pathology , Massachusetts General Hospital, Harvard Medical School , Boston , Massachusetts , USA.,b Department of Urology , Massachusetts General Hospital, Harvard Medical School , Boston , Massachusetts , USA
| | - Jianheng Ye
- b Department of Urology , Massachusetts General Hospital, Harvard Medical School , Boston , Massachusetts , USA.,c Department of Urology , Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People's Hospital, Guangzhou Medical University , Guangzhou , Guangdong , China
| | - Zongwei Wang
- b Department of Urology , Massachusetts General Hospital, Harvard Medical School , Boston , Massachusetts , USA
| | - Sharron X Lin
- b Department of Urology , Massachusetts General Hospital, Harvard Medical School , Boston , Massachusetts , USA
| | - Min Lu
- d Department of Pathology , School of Basic Medical Sciences, Peking University Health Science Center , Beijing , China
| | - Yingke Liang
- b Department of Urology , Massachusetts General Hospital, Harvard Medical School , Boston , Massachusetts , USA.,c Department of Urology , Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People's Hospital, Guangzhou Medical University , Guangzhou , Guangdong , China
| | - Xuejin Zhu
- b Department of Urology , Massachusetts General Hospital, Harvard Medical School , Boston , Massachusetts , USA.,c Department of Urology , Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People's Hospital, Guangzhou Medical University , Guangzhou , Guangdong , China
| | - Aria F Olumi
- b Department of Urology , Massachusetts General Hospital, Harvard Medical School , Boston , Massachusetts , USA
| | - Wei-de Zhong
- c Department of Urology , Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People's Hospital, Guangzhou Medical University , Guangzhou , Guangdong , China
| | - Chin-Lee Wu
- a Department of Pathology , Massachusetts General Hospital, Harvard Medical School , Boston , Massachusetts , USA.,b Department of Urology , Massachusetts General Hospital, Harvard Medical School , Boston , Massachusetts , USA
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26
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Chen J, Cui Y, Li P, Liu L, Li C, Zu X. Expression and clinical significance of androgen receptor in bladder cancer: A meta-analysis. Mol Clin Oncol 2017; 7:919-927. [PMID: 29181189 DOI: 10.3892/mco.2017.1389] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2017] [Accepted: 06/28/2017] [Indexed: 12/19/2022] Open
Abstract
Emerging evidence has demonstrated that androgen receptor (AR) is a promising therapeutic target for bladder cancer. However, the relationship between AR expression and its clinical significance remains controversial. The present in-depth meta-analysis aimed to investigate the correlation between AR expression and clinicopathological features, as well as prognostic value in bladder cancer. A systematic search was performed from PubMed, Web of Knowledge, Embase and the Cochrane Central Search Library by January 2017. The correlation between AR expression and tumor stage, tumor grade, recurrence free survival and progression free survival for patients with bladder cancer was evaluated. A total of 12 relevant studies with 1,652 patient samples were included. AR expression positively correlated with low tumor grade [odds ratio (OR), 1.95; 95% confidence interval (CI), 1.36-2.81], low tumor stage (OR, 2.06; 95% CI, 1.02-4.16) and low recurrence rate [hazard ratio (HR), 0.48; 95% CI, 0.31-0.75] in Caucasian patients. While, its expression had no significant impact on cancer susceptibility (OR, 1.62; 95% CI, 0.19-13.72; P=0.44) and progression-free survival (HR, 1.20; 95% CI, 0.86-1.66; P=0.77). The present meta-analysis indicated that AR expression correlates with tumor grade, clinical stage and recurrence rates in the specified population and classification system. Further studies are required to determine the precise role of AR in bladder cancer.
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Affiliation(s)
- Jinbo Chen
- Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China.,Department of Pathology and Laboratory Medicine, The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY 14620, USA
| | - Yu Cui
- Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Peng Li
- Minimally Invasive Urology Center, Shandong Provincial Hospital, Shandong University School of Medicine, Jinan, Shandong 250021, P.R. China
| | - Longfei Liu
- Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Chao Li
- Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Xiongbing Zu
- Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
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Ide H, Inoue S, Miyamoto H. Histopathological and prognostic significance of the expression of sex hormone receptors in bladder cancer: A meta-analysis of immunohistochemical studies. PLoS One 2017; 12:e0174746. [PMID: 28362839 PMCID: PMC5375178 DOI: 10.1371/journal.pone.0174746] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2016] [Accepted: 03/14/2017] [Indexed: 12/26/2022] Open
Abstract
Objective Emerging preclinical evidence suggests the involvement of sex hormones and their receptor signals in the development and progression of bladder cancer. Meanwhile, previous studies have demonstrated conflicting results on the relationship between the status of sex hormone receptors in urothelial tumors and histopathological characteristics of the tumors or patient outcomes. We therefore conducted this meta-analysis to assess the clinicopathological impact of the expression of androgen receptor (AR) and estrogen receptors (ERs) in bladder cancer. Methods A comprehensive literature search in databases (i.e. PubMed, Web of Science, Cochrane) was performed for all immunohistochemical studies stained for AR, ERα, and/or ERβ in surgically resected bladder cancer specimens and analyzed for patient outcomes. We selected eligible studies in accordance with the PRISMA guidelines and analyzed data using R software. Results A total of 2,049 patients from 13 retrospective studies were included in this meta-analysis. The difference in ERα expression between non-tumors and tumors was significant [odds ratio (OR) = 0.412; P<0.001], while those of AR (OR = 3.256; P = 0.336) or ERβ (OR = 0.580; P = 0.674) were not statistically significant. AR positivity in tumors was strongly correlated with gender (male vs. female: OR = 0.658; P = 0.027) or tumor grade (low-grade vs. high-grade: OR = 0.575; P<0.001). ERβ positive rates were significantly higher in high-grade (OR = 2.169; P<0.001) and muscle-invasive (OR = 3.104; P<0.001) tumors than in low-grade and non-muscle-invasive tumors, respectively. Survival analysis in patients with non-muscle-invasive bladder cancer revealed associations between AR expression and better recurrence-free survival [hazard ration (HR) = 0.593; P = 0.006) as well as between ERβ expression and worse recurrence-free (HR = 1.573; P = 0.013) or progression-free (HR = 4.148; P = 0.089) survivals. Conclusions These data suggest down-regulation of ERα expression in bladder tumors, compared with non-neoplastic urothelial tissues. AR or ERβ expression was down- or up-regulated, respectively, in high-grade and/or muscle-invasive bladder cancers. Moreover, immunohistochemistry of AR/ERβ in surgical specimens may serve as prognosticators in patients with non-muscle-invasive bladder tumor.
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Affiliation(s)
- Hiroki Ide
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
- The Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
| | - Satoshi Inoue
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
- The Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
- Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, New York, United States of America
- The Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, United States of America
| | - Hiroshi Miyamoto
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
- The Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
- Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, New York, United States of America
- The Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, United States of America
- Department Urology, University of Rochester Medical Center, Rochester, New York, United States of America
- * E-mail:
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28
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Kameyama K, Horie K, Mizutani K, Kato T, Fujita Y, Kawakami K, Kojima T, Miyazaki T, Deguchi T, Ito M. Enzalutamide inhibits proliferation of gemcitabine-resistant bladder cancer cells with increased androgen receptor expression. Int J Oncol 2016; 50:75-84. [PMID: 27909718 DOI: 10.3892/ijo.2016.3781] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2016] [Accepted: 11/17/2016] [Indexed: 11/05/2022] Open
Abstract
Advanced bladder cancer is treated mainly with gemcitabine and cisplatin, but most patients eventually become resistance. Androgen receptor (AR) signaling has been implicated in bladder cancer as well as other types of cancer including prostate cancer. In this study, we investigated the expression and role of AR in gemcitabine-resistant bladder cancer cells and also the potential of enzalutamide, an AR inhibitor, as a therapeutic for the chemoresistance. First of all, we established gemcitabine-resistant T24 cells (T24GR) from T24 bladder cancer cells and performed gene expression profiling. Microarray analysis revealed upregulation of AR expression in T24GR cells compared with T24 cells. AR mRNA and protein expression was confirmed to be increased in T24GR cells, respectively, by quantitative RT-PCR and western blot analysis, which was associated with more potent AR transcriptional activity as measured by luciferase reporter assay. The copy number of AR gene in T24GR cells determined by PCR was twice as many as that of T24 cells. AR silencing by siRNA transfection resulted in inhibition of proliferation of T24GR cells. Cell culture in charcoal-stripped serum and treatment with enzalutamide inhibited growth of T24GR cells, which was accompanied by cell cycle arrest. AR transcriptional activity was found to be reduced in T24GR cells by enzalutamide treatment. Lastly, enzalutamide also inhibited cell proliferation of HTB5 bladder cancer cells that express AR and possess intrinsic resistance to gemcitabine. Our results suggest that enzalutamide may have the potential to treat patients with advanced gemcitabine-resistant bladder cancer with increased AR expression.
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Affiliation(s)
- Koji Kameyama
- Department of Urology, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1193, Japan
| | - Kengo Horie
- Department of Urology, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1193, Japan
| | - Kosuke Mizutani
- Department of Urology, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1193, Japan
| | - Taku Kato
- Department of Urology, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1193, Japan
| | - Yasunori Fujita
- Research Team for Mechanism of Aging, Tokyo Metropolitan Institute of Gerontology, Itabashi-ku, Tokyo 173-0015, Japan
| | - Kyojiro Kawakami
- Research Team for Mechanism of Aging, Tokyo Metropolitan Institute of Gerontology, Itabashi-ku, Tokyo 173-0015, Japan
| | - Toshio Kojima
- Health Support Center, Toyohashi University of Technology, Tenpaku-cho, Toyohashi, Aichi 441-8580, Japan
| | - Tatsuhiko Miyazaki
- Division of Pathology, Gifu University Hospital, Gifu, Gifu 501-1194, Japan
| | - Takashi Deguchi
- Department of Urology, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1193, Japan
| | - Masafumi Ito
- Research Team for Mechanism of Aging, Tokyo Metropolitan Institute of Gerontology, Itabashi-ku, Tokyo 173-0015, Japan
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29
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Shiota M, Yokomizo A, Takeuchi A, Inokuchi J, Tatsugami K, Ohga S, Sasaki T, Nakamura K, Honda H, Eto M. Smoking effect on secondary bladder cancer after external beam radiotherapy for prostate cancer. Jpn J Clin Oncol 2016; 46:952-957. [DOI: 10.1093/jjco/hyw098] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2016] [Accepted: 06/24/2016] [Indexed: 12/15/2022] Open
Affiliation(s)
- Masaki Shiota
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka
| | - Akira Yokomizo
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka
| | - Ario Takeuchi
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka
| | - Junichi Inokuchi
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka
| | - Katsunori Tatsugami
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka
| | - Saiji Ohga
- Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Tomonari Sasaki
- Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Katsumasa Nakamura
- Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Hiroshi Honda
- Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masatoshi Eto
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka
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30
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Kawahara T, Shareef HK, Aljarah AK, Ide H, Li Y, Kashiwagi E, Netto GJ, Zheng Y, Miyamoto H. ELK1 is up-regulated by androgen in bladder cancer cells and promotes tumor progression. Oncotarget 2016; 6:29860-76. [PMID: 26342199 PMCID: PMC4745768 DOI: 10.18632/oncotarget.5007] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2015] [Accepted: 08/12/2015] [Indexed: 12/15/2022] Open
Abstract
Little is known about biological significance of ELK1, a transcriptional factor that activates downstream targets including c-fos proto-oncogene, in bladder cancer. Recent preclinical evidence also suggests the involvement of androgen receptor (AR) signaling in bladder cancer progression. In this study, we aim to investigate the functions of ELK1 in bladder cancer growth and their regulation by AR signals. Immunohistochemistry in bladder tumor specimens showed that the levels of phospho-ELK1 (p-ELK1) expression were significantly elevated in urothelial neoplasms, compared with non-neoplastic urothelium tissues, and were also correlated with AR positivity. Patients with p-ELK1-positive non-muscle-invasive and muscle-invasive tumors had significantly higher risks for tumor recurrence and progression, respectively. In AR-positive bladder cancer cell lines, dihydrotestosterone treatment increased ELK1 expression (mRNA, protein) and its nuclear translocation, ELK1 transcriptional activity, and c-fos expression, which was restored by an anti-androgen hydroxyflutamide. ELK1 silencing via short hairpin RNA (shRNA) resulted in decreases in cell viability/colony formation, and cell migration/invasion as well as an increase in apoptosis. Importantly, ELK1 appears to require activated AR to regulate bladder cancer cell proliferation, but not cell migration. Androgen also failed to significantly induce AR transactivation in ELK1-knockdown cells. In accordance with our in vitro findings, ELK1-shRNA expression considerably retarded tumor formation as well as its growth in xenograft-bearing male mice. Our results suggest that ELK1 plays an important role in bladder tumorigenesis and cancer progression, which is further induced by AR activation. Accordingly, ELK1 inhibition, together with AR inactivation, has the potential of being a therapeutic approach for bladder cancer.
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Affiliation(s)
- Takashi Kawahara
- Departments of Pathology and Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.,Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA.,Department of Urology, Yokohama City University School of Medicine, Yokohama, Japan
| | - Hasanain Khaleel Shareef
- Departments of Pathology and Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.,Department of Biology, University of Babylon College of Science for Women, Babylon, Iraq
| | - Ali Kadhim Aljarah
- Departments of Pathology and Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.,Department of Biology, University of Baghdad College of Science, Baghdad, Iraq
| | - Hiroki Ide
- Departments of Pathology and Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Yi Li
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA.,Department of Urology, 2nd Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Eiji Kashiwagi
- Departments of Pathology and Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - George J Netto
- Departments of Pathology and Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Yichun Zheng
- Departments of Pathology and Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.,Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA.,Department of Urology, 2nd Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Hiroshi Miyamoto
- Departments of Pathology and Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.,Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA
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31
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Shiota M, Kiyoshima K, Yokomizo A, Takeuchi A, Kashiwagi E, Dejima T, Takahashi R, Inokuchi J, Tatsugami K, Eto M. Suppressed Recurrent Bladder Cancer after Androgen Suppression with Androgen Deprivation Therapy or 5α-Reductase Inhibitor. J Urol 2016; 197:308-313. [PMID: 27506696 DOI: 10.1016/j.juro.2016.08.006] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/01/2016] [Indexed: 10/21/2022]
Abstract
PURPOSE We determined whether intravesical recurrence is affected by inhibition of androgen signaling among men with nonmuscle invasive bladder cancer. MATERIALS AND METHODS We examined the intravesical recurrence rate among men treated with or without androgen suppression therapy by androgen deprivation therapy for prostate cancer or 5α-reductase inhibitor dutasteride for benign prostatic hyperplasia. RESULTS We studied 228 men, including 32 with and 196 without androgen suppression therapy. During a median followup of 3.6 and 3.0 years intravesical recurrence developed in 4 (12.5%) and 59 men (30.1%) with and without androgen suppression therapy, respectively. On multivariate analysis multiple tumors (HR 1.82, p = 0.027), a large tumor (HR 2.13, p = 0.043) and ever smoking (HR 2.45, p = 0.020) as well as the presence of androgen suppression therapy (HR 0.36, p = 0.024) were independent risk factors for intravesical recurrence. Notably, tumor progressed to muscle invasive bladder cancer in 6 men (3.1%) without androgen suppression therapy. No man with androgen suppression therapy progressed to muscle invasive bladder cancer. CONCLUSIONS Our study suggests the possibility of androgen suppression therapy as prophylaxis for intravesical recurrence of bladder cancer. Further explorations are warranted of the prophylactic effect of androgen suppression therapy on bladder cancer pathogenesis.
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Affiliation(s)
- Masaki Shiota
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
| | - Keijiro Kiyoshima
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Akira Yokomizo
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Ario Takeuchi
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Eiji Kashiwagi
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takashi Dejima
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Ryosuke Takahashi
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Junichi Inokuchi
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Katsunori Tatsugami
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masatoshi Eto
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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32
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Ou Z, Wang Y, Liu L, Li L, Yeh S, Qi L, Chang C. Tumor microenvironment B cells increase bladder cancer metastasis via modulation of the IL-8/androgen receptor (AR)/MMPs signals. Oncotarget 2016; 6:26065-78. [PMID: 26305549 PMCID: PMC4694886 DOI: 10.18632/oncotarget.4569] [Citation(s) in RCA: 84] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2015] [Accepted: 07/06/2015] [Indexed: 12/11/2022] Open
Abstract
While B cells in the tumor microenvironment may play important roles in cancer progression, their impacts on the bladder cancer (BCa) metastasis remain unclear. Here we found from human clinical BCa samples that BCa tissues could recruit more B cells than the surrounding normal bladder tissues and the in vitro co-culture assay also demonstrated that B cells could be recruited more easily towards BCa cells compared to normal bladder cells. Chamber invasion and 3D invasion assays showed the recruited B cells could then significantly increase the BCa cell invasion. Mechanism dissection found that recruited B cells could increase IL-8/androgen receptor (AR) signals in BCa cells that could then promote the expression of metastasis genes including MMP1 and MMP13. Blocking the IL-8/AR/MMPs signals either by anti-IL-8 neutralizing antibody, AR-siRNA, or MMPs inhibitors all partially reversed the infiltrating B cells capacity to increase the BCa cell invasion. The in vivo data from orthotopically xenografted BCa mouse model also confirmed that infiltrating B cells could increase BCa cell invasion via increasing AR signals. Together, these results demonstrate the key roles of B cells within the bladder tumor microenvironment that increase the BCa metastasis and may help us to develop the potential therapies via targeting these newly identified IL-8/AR/MMPs signals to better battle the BCa progression.
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Affiliation(s)
- Zhenyu Ou
- Departments of Urology and Plastic Surgery, Xiangya Hospital, Central South University, Changsha, China.,George Whipple Lab for Cancer Research, Departments of Pathology and Urology, University of Rochester Medical Center, Rochester, NY, USA
| | - Yongjie Wang
- Departments of Urology and Plastic Surgery, Xiangya Hospital, Central South University, Changsha, China.,George Whipple Lab for Cancer Research, Departments of Pathology and Urology, University of Rochester Medical Center, Rochester, NY, USA
| | - Longfei Liu
- Departments of Urology and Plastic Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Lei Li
- George Whipple Lab for Cancer Research, Departments of Pathology and Urology, University of Rochester Medical Center, Rochester, NY, USA
| | - Shuyuan Yeh
- George Whipple Lab for Cancer Research, Departments of Pathology and Urology, University of Rochester Medical Center, Rochester, NY, USA
| | - Lin Qi
- Departments of Urology and Plastic Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Chawnshang Chang
- George Whipple Lab for Cancer Research, Departments of Pathology and Urology, University of Rochester Medical Center, Rochester, NY, USA.,Sex hormone Research Center, China Medical University/Hospital, Taichung, Taiwan
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33
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Shiota M, Yokomizo A, Takeuchi A, Imada K, Kiyoshima K, Inokuchi J, Tatsugami K, Ohga S, Nakamura K, Honda H, Naito S. Secondary bladder cancer after anticancer therapy for prostate cancer: reduced comorbidity after androgen-deprivation therapy. Oncotarget 2016; 6:14710-9. [PMID: 25900243 PMCID: PMC4546499 DOI: 10.18632/oncotarget.3817] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2015] [Accepted: 03/03/2015] [Indexed: 11/25/2022] Open
Abstract
Radiotherapy for prostate cancer is associated with an increased incidence of secondary bladder cancer (BC). We investigated the incidence, clinicopathological characteristics, and prognosis of BC after radiotherapy, surgical therapy, and primary androgen-deprivation therapy (ADT) for prostate cancer. This study included 1,334 Japanese patients with prostate cancer treated with radiotherapy (n=631), surgical therapy (n=437), and primary ADT (n=266). During the median follow-up period of 51.2, 44.8, and 45.5 months, secondary BC occurred in 14 (2.2%), 5 (1.1%), and 0 (0%) of patients with prostate cancer treated with radiotherapy, surgical therapy, and primary ADT, respectively. The 10-year BC-free survival rate was 91.3% in the radiotherapy group, 97.4% in the surgical therapy group, and 100% in the primary ADT group. The rates of intravesical recurrence, progression to muscle-invasive BC, and BC-specific death might be higher in secondary BC after radiotherapy compared with after surgical therapy. There was a significant difference in the incidence of secondary BC among different therapeutic modalities for prostate cancer in Japanese men, indicating significantly lower comorbidity rates of secondary BC after primary ADT for prostate cancer compared with radiotherapy.
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Affiliation(s)
- Masaki Shiota
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Akira Yokomizo
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Ario Takeuchi
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kenjiro Imada
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Keijiro Kiyoshima
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Junichi Inokuchi
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Katsunori Tatsugami
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Saiji Ohga
- Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Katsumasa Nakamura
- Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Hiroshi Honda
- Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Seiji Naito
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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34
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Izumi K, Ito Y, Miyamoto H, Miyoshi Y, Ota J, Moriyama M, Murai T, Hayashi H, Inayama Y, Ohashi K, Yao M, Uemura H. Expression of androgen receptor in non-muscle-invasive bladder cancer predicts the preventive effect of androgen deprivation therapy on tumor recurrence. Oncotarget 2016; 7:14153-60. [PMID: 26885620 PMCID: PMC4924704 DOI: 10.18632/oncotarget.7358] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2015] [Accepted: 01/29/2016] [Indexed: 12/21/2022] Open
Abstract
Our recent retrospective study revealed a significantly reduced risk of bladder cancer (BC) recurrence in men who received androgen deprivation therapy (ADT) for their prostate cancer. However, whether androgen receptor (AR) signals contributed to the preventive effect of ADT remained unclear because ADT could reduce serum estrogens as well. The purpose of this study is to investigate the associations between the expression of AR/estrogen receptors (ERs) and BC recurrence in patients treated with ADT. We immunohistochemically stained 72 BCs and 42 corresponding normal urothelial tissues. AR/ERα/ERβ were positive in 44(61%)/22(31%)/39(54%) tumors and 35(83%)/24(57%)/34(81%) corresponding normal urothelial tissues, respectively. There were no statistically significant correlations between AR/ERα/ERβ expression and clinicopathological features of BC. With a median follow-up of 31.3 months, 12 (43%) of 28 patients with AR-negative tumor versus 11 (23%) of 44 patients with AR-positive tumor experienced BC recurrence. Thus, patients with AR-positive tumor had a significantly lower risk of BC recurrence (P=0.031), compared with those with AR-negative tumor. Meanwhile, the expression of ERα/ERβ in tumors and that of AR/ERα/ERβ in normal urothelial tissues were not significantly correlated with BC recurrence. A multivariate analysis revealed AR positivity in tumors as an independent prognosticator (hazard ratio: 0.27; 95% confidence interval: 0.11-0.67) for BC recurrence. These results indicate that ADT prevents BC recurrence via the AR pathway, but not via the ERα/ERβ pathways.
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Affiliation(s)
- Koji Izumi
- Department of Urology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
- Department of Urology, Yokohama Municipal Citizen's Hospital, Yokohama, Japan
| | - Yusuke Ito
- Department of Urology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Hiroshi Miyamoto
- Departments of Pathology and Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Yasuhide Miyoshi
- Department of Urology, Yokohama City University Medical Center, Yokohama, Japan
| | - Junichi Ota
- Department of Urology, Yokohama Municipal Citizen's Hospital, Yokohama, Japan
| | - Masatoshi Moriyama
- Department of Urology, Yokohama Municipal Citizen's Hospital, Yokohama, Japan
| | - Tetsuo Murai
- Department of Urology, International Goodwill Hospital, Yokohama, Japan
| | - Hiroyuki Hayashi
- Department of Pathology, Yokohama Municipal Citizen's Hospital, Yokohama, Japan
| | - Yoshiaki Inayama
- Department of Pathology, Yokohama City University Medical Center, Yokohama, Japan
| | - Kenichi Ohashi
- Department of Pathology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Masahiro Yao
- Department of Urology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Hiroji Uemura
- Department of Urology, Yokohama City University Medical Center, Yokohama, Japan
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35
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Affiliation(s)
- Edward M. Messing
- Correspondence to: Edward M. Messing, University of Rochester Medical Center, Rochester, USA. E-mail:
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36
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Ide H, Miyamoto H. Steroid Hormone Receptor Signals as Prognosticators for Urothelial Tumor. DISEASE MARKERS 2015; 2015:840640. [PMID: 26770009 PMCID: PMC4685115 DOI: 10.1155/2015/840640] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/18/2015] [Accepted: 11/18/2015] [Indexed: 12/18/2022]
Abstract
There is a substantial amount of preclinical or clinical evidence suggesting that steroid hormone receptor-mediated signals play a critical role in urothelial tumorigenesis and tumor progression. These receptors include androgen receptor, estrogen receptors, glucocorticoid receptor, progesterone receptor, vitamin D receptor, retinoid receptors, peroxisome proliferator-activated receptors, and others including orphan receptors. In particular, studies using urothelial cancer tissue specimens have demonstrated that elevated or reduced expression of these receptors as well as alterations of their upstream or downstream pathways correlates with patient outcomes. This review summarizes and discusses available data suggesting that steroid hormone receptors and related signals serve as biomarkers for urothelial carcinoma and are able to predict tumor recurrence or progression.
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Affiliation(s)
- Hiroki Ide
- Departments of Pathology and Urology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Hiroshi Miyamoto
- Departments of Pathology and Urology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
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37
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Androgen deprivation therapy prevents bladder cancer recurrence. Oncotarget 2015; 5:12665-74. [PMID: 25557268 PMCID: PMC4350350 DOI: 10.18632/oncotarget.2851] [Citation(s) in RCA: 96] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2014] [Accepted: 12/03/2014] [Indexed: 01/07/2023] Open
Abstract
Although accumulating preclinical evidence indicates the involvement of androgen receptor signals in bladder cancer (BC) development, its clinical relevance remains unclear. We aimed to evaluate the predictive role of androgen deprivation therapy (ADT) in BC recurrence in prostate cancer (PC) patients. We retrospectively reviewed 20,328 patients with PC diagnosed during 1991–2013 and identified 239 (1.2%) men having primary BC. After excluding ineligible patients, 162 patients made up a final cohort. With a median follow-up of 62 months, 38 (50%) of 76 control patients without ADT experienced BC recurrence, while 19 (22%) of 86 did in ADT group. Thus, patients having received ADT for their PC showed a significantly lower risk of BC recurrence (5-year actuarial recurrence-free survival: 76% v 40%; P < 0.001) and also had a significantly smaller number of recurrence episodes (5-year cumulative recurrence: 0.44 v 1.54; P < 0.001), compared to the control patients. A multivariable analysis revealed ADT as an independent prognosticator (hazard ratio, 0.29; 95% confidence interval, 0.17–0.49) for BC recurrence. This is the first clinical study showing that ADT significantly reduces the risk of BC recurrence.
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Zheng Y, Ishiguro H, Ide H, Inoue S, Kashiwagi E, Kawahara T, Jalalizadeh M, Reis LO, Miyamoto H. Compound A Inhibits Bladder Cancer Growth Predominantly via Glucocorticoid Receptor Transrepression. Mol Endocrinol 2015; 29:1486-1497. [PMID: 26322830 PMCID: PMC5414678 DOI: 10.1210/me.2015-1128] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2015] [Accepted: 08/27/2015] [Indexed: 01/05/2023] Open
Abstract
Recent evidence indicates that glucocorticoids (GCs) suppress bladder cancer cell invasion through the GC receptor (GR) pathway, whereas androgen-mediated androgen receptor (AR) signals induce bladder tumor progression. In this study, we assessed the effects of 2-(4-acetoxyphenyl)-2-chloro-N-methyl-ethylammonium chloride (compound A [CpdA]), which was shown to function as not only a GR modulator but also an AR antagonist, on the growth of bladder cancer. In GR/AR-positive cells, CpdA strongly inhibited cell proliferation and colony formation as well as increased G1 phase-arrested cell population and apoptosis. Specifically, CpdA at 1μM decreased cell viability of TCCSUP/UMUC3-control-short hairpin RNA (shRNA), TCCSUP/UMUC3-GR-shRNA, and TCCSUP/UMUC3-AR-shRNA by 50%/67%, 25%/26%, and 38%/58%, respectively. CpdA also inhibited cell migration and invasion of GR/AR-positive (up to 61% decrease) and GR-positive/AR-silencing (up to 51% decrease) lines and, less strongly, those of GR-silencing/AR-positive lines (up to 35% decrease). Additionally, in UMUC3-control xenograft-bearing male mice, CpdA more strongly suppressed tumor growth than dexamethasone or hydroxyflutamide. In reporter gene assays, CpdA failed to induce GR transactivation, whereas it antagonized dihydrotestosterone-enhanced AR transactivation. In contrast, CpdA reduced nuclear factor (NF)-κB and activator protein 1 transcriptional activities, indicating induction of GR-mediated transrepression. Correspondingly, the expression of NF-κB-related molecules, matrix metalloproteinase-2, matrix metalloproteinase-9, interleukin-6, and vascular endothelial growth factor, was significantly down-regulated by CpdA in control lines but not in GR-silencing cells. Moreover, coimmunoprecipitation showed that CpdA promoted the interactions between GR and NF-κB. Thus, CpdA likely inhibits bladder cancer growth predominantly via inducing GR transrepression and at least partially mediated through the AR pathway, suggesting its effects more beneficial than GCs/pure GR ligands or AR antagonists.
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Affiliation(s)
- Yichun Zheng
- Department of Urology (Y.Z.), Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China; Departments of Pathology and Urology (Y.Z., H.Is., H.Id., S.I., E.K., T.K., M.J., L.O.R., H.M.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21287; Department of Pathology and Laboratory Medicine (Y.Z., H.Is., T.K., H.M.), University of Rochester Medical Center, Rochester, New York 14642; and Photocatalyst Group (H.Is.), Kanagawa Academy of Science and Technology, Kawasaki 210-0821, Japan
| | - Hitoshi Ishiguro
- Department of Urology (Y.Z.), Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China; Departments of Pathology and Urology (Y.Z., H.Is., H.Id., S.I., E.K., T.K., M.J., L.O.R., H.M.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21287; Department of Pathology and Laboratory Medicine (Y.Z., H.Is., T.K., H.M.), University of Rochester Medical Center, Rochester, New York 14642; and Photocatalyst Group (H.Is.), Kanagawa Academy of Science and Technology, Kawasaki 210-0821, Japan
| | - Hiroki Ide
- Department of Urology (Y.Z.), Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China; Departments of Pathology and Urology (Y.Z., H.Is., H.Id., S.I., E.K., T.K., M.J., L.O.R., H.M.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21287; Department of Pathology and Laboratory Medicine (Y.Z., H.Is., T.K., H.M.), University of Rochester Medical Center, Rochester, New York 14642; and Photocatalyst Group (H.Is.), Kanagawa Academy of Science and Technology, Kawasaki 210-0821, Japan
| | - Satoshi Inoue
- Department of Urology (Y.Z.), Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China; Departments of Pathology and Urology (Y.Z., H.Is., H.Id., S.I., E.K., T.K., M.J., L.O.R., H.M.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21287; Department of Pathology and Laboratory Medicine (Y.Z., H.Is., T.K., H.M.), University of Rochester Medical Center, Rochester, New York 14642; and Photocatalyst Group (H.Is.), Kanagawa Academy of Science and Technology, Kawasaki 210-0821, Japan
| | - Eiji Kashiwagi
- Department of Urology (Y.Z.), Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China; Departments of Pathology and Urology (Y.Z., H.Is., H.Id., S.I., E.K., T.K., M.J., L.O.R., H.M.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21287; Department of Pathology and Laboratory Medicine (Y.Z., H.Is., T.K., H.M.), University of Rochester Medical Center, Rochester, New York 14642; and Photocatalyst Group (H.Is.), Kanagawa Academy of Science and Technology, Kawasaki 210-0821, Japan
| | - Takashi Kawahara
- Department of Urology (Y.Z.), Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China; Departments of Pathology and Urology (Y.Z., H.Is., H.Id., S.I., E.K., T.K., M.J., L.O.R., H.M.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21287; Department of Pathology and Laboratory Medicine (Y.Z., H.Is., T.K., H.M.), University of Rochester Medical Center, Rochester, New York 14642; and Photocatalyst Group (H.Is.), Kanagawa Academy of Science and Technology, Kawasaki 210-0821, Japan
| | - Mehrsa Jalalizadeh
- Department of Urology (Y.Z.), Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China; Departments of Pathology and Urology (Y.Z., H.Is., H.Id., S.I., E.K., T.K., M.J., L.O.R., H.M.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21287; Department of Pathology and Laboratory Medicine (Y.Z., H.Is., T.K., H.M.), University of Rochester Medical Center, Rochester, New York 14642; and Photocatalyst Group (H.Is.), Kanagawa Academy of Science and Technology, Kawasaki 210-0821, Japan
| | - Leonardo O Reis
- Department of Urology (Y.Z.), Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China; Departments of Pathology and Urology (Y.Z., H.Is., H.Id., S.I., E.K., T.K., M.J., L.O.R., H.M.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21287; Department of Pathology and Laboratory Medicine (Y.Z., H.Is., T.K., H.M.), University of Rochester Medical Center, Rochester, New York 14642; and Photocatalyst Group (H.Is.), Kanagawa Academy of Science and Technology, Kawasaki 210-0821, Japan
| | - Hiroshi Miyamoto
- Department of Urology (Y.Z.), Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China; Departments of Pathology and Urology (Y.Z., H.Is., H.Id., S.I., E.K., T.K., M.J., L.O.R., H.M.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21287; Department of Pathology and Laboratory Medicine (Y.Z., H.Is., T.K., H.M.), University of Rochester Medical Center, Rochester, New York 14642; and Photocatalyst Group (H.Is.), Kanagawa Academy of Science and Technology, Kawasaki 210-0821, Japan
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Sukocheva OA, Li B, Due SL, Hussey DJ, Watson DI. Androgens and esophageal cancer: What do we know? World J Gastroenterol 2015; 21:6146-6156. [PMID: 26034350 PMCID: PMC4445092 DOI: 10.3748/wjg.v21.i20.6146] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2015] [Revised: 03/27/2015] [Accepted: 04/16/2015] [Indexed: 02/06/2023] Open
Abstract
Significant disparities exist between genders for the development and progression of several gastro-intestinal (GI) diseases including cancer. Differences in incidence between men vs women for colon, gastric and hepatocellular cancers suggest a role for steroid sex hormones in regulation of GI carcinogenesis. Involvement of intrinsic gender-linked mechanisms is also possible for esophageal adenocarcinoma as its incidence is disproportionally high among men. However, the cause of the observed gender differences and the potential role of androgens in esophageal carcinogenesis remains unclear, even though the cancer-promoting role of androgen receptors (AR) shown in other cancers such as prostate and bladder suggests this aspect warrants exploration. Several studies have demonstrated expression of ARs in esophageal cancer. However, only one study has suggested a potential link between AR signaling and outcome - poorer prognosis. Two groups have analyzed data from cohorts with prostate cancer and one of these found a decreased incidence of esophageal squamous and adenocarcinoma after androgen deprivation therapy. However, very limited information is available about the effects of androgen and AR-initiated signaling on esophageal cancer cell growth in vitro and in vivo. Possible mechanisms for androgens/AR involvement in the regulation of esophageal cancer growth are considered, and the potential use of AR as a prognostic factor and clinical target is highlighted, although insufficient evidence is available to support clinical trials of novel therapies. As esophageal adenocarcinoma is a gender linked cancer with a large male predominance further studies are warranted to clarify the role of androgens and ARs in shaping intracellular signaling and genomic responses in esophageal cancer.
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Abstract
PURPOSE OF REVIEW To review and summarize current knowledge on gender differences and sex steroid hormones in nonmuscle invasive bladder cancer. RECENT FINDINGS Beyond the proven role of gender as a risk factor for the development of bladder cancer, recent studies indicate that women present with more advanced bladder cancer tumor stages than men, which may be due to differences in both bladder cancer care and biology. In addition, female gender has been identified as an independent prognostic factor for both recurrence and progression and may be associated with worse response to Bacillus Calmette-Guérin instillation therapy. Overall, sex steroid hormones and their receptors impact bladder carcinogenesis, recurrence and progression. Basic and transitional research evidence suggests that estrogens may initially protect against bladder cancer development, but later promote bladder cancer progression. Androgens, in contrast, seem to initiate and drive bladder cancer with its receptor playing a central role. Promising novel research shows a potential role of sex steroid hormones as therapeutic targets. SUMMARY Whereas men are more likely to develop bladder cancer, women present generally with more advanced disease and have worse oncologic outcomes even after adjusting for tumor stage. Sex steroid hormones and their receptors play an active role in bladder cancer development and progression and represent attractive therapeutic targets for gender-specific care.
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Abdel-Hamid AAM, Ali EMT. Effect of testosterone therapy on the urinary bladder in experimental hypogonadism of rats. J Mol Histol 2015; 46:263-72. [PMID: 25805595 DOI: 10.1007/s10735-015-9617-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2015] [Accepted: 03/17/2015] [Indexed: 11/24/2022]
Abstract
Testosterone (T) deficiency is prevalent particularly in elderly men and lead to physical and sexual morbidities. Although low levels of T are associated with low urinary tract symptoms, the correlation between T deficiency and bladder dysfunction is not clearly identified. The aim of this study was to investigate the effect of high dose testosterone replacement therapy (TRT) on the histological structure of the UB in castrated rats. Twenty-five adult male rats were divided into three groups: control, castrated and castrated + TRT. T was administrated in high dose (100 mg/kg) two intramuscular injections/week for 60 days. UB sections were prepared and stained with H&E, Masson's trichrome and immunohistochemical detection of Cytokeratin 20 (Ck20). All data were morphometrically and statistically analyzed. In castrated group, significant atrophy of the urothelium (P < 0.001) accompanied with widening of the corium were observed. The smooth muscle appeared thin with marked increase in the collagen fibers. On treating the castrated group with TRT, atypical Ck20 expression as well as significant increase in urothelial thickness (P < 0.05) and smooth muscle/collagen ratio (P < 0.001) were detected. In castrated rat model, high dose TRT has a positive effect on the UB smooth muscle rather than the urothelium which acquired atypical patterns.
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Affiliation(s)
- Ahmed A M Abdel-Hamid
- Department of Histology and Cell Biology, Faculty of Medicine, Mansoura University, P.O. 35516, Mansoura, Egypt,
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Kawahara T, Kashiwagi E, Ide H, Li Y, Zheng Y, Miyamoto Y, Netto GJ, Ishiguro H, Miyamoto H. Cyclosporine A and tacrolimus inhibit bladder cancer growth through down-regulation of NFATc1. Oncotarget 2015; 6:1582-93. [PMID: 25638160 PMCID: PMC4359316 DOI: 10.18632/oncotarget.2750] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2014] [Accepted: 11/15/2014] [Indexed: 11/27/2022] Open
Abstract
The functional role of nuclear factor of activated T-cells (NFAT), a key regulator of the immune response, in bladder cancer progression remains uncertain. In this study, we assessed biological significance of NFAT in human bladder cancer. Immunohistochemistry detected nuclear/cytoplasmic NFATc1 signals in 14 (21.5%)/34 (52.3%), respectively, of 65 muscle-invasive bladder carcinomas and showed that patients with nuclear NFATc1-positive tumor had a significantly higher risk of disease progression (P = 0.006). In bladder cancer cell lines, cyclosporine A (CsA) and tacrolimus (FK506), immunosuppressant drugs/non-selective NFAT inhibitors, attenuated NFATc1 expression and its nuclear translocation, NFAT transcriptional activity, and the expression of cyclooxygenase-2 and c-myc, downstream targets of NFATc1. NFAT inhibition via NFATc1-small interfering RNA (siRNA) or treatment with these NFAT inhibitors resulted in decreases in cell viability/colony formation, cell migration/invasion, and the expression/activity of MMP-2 and MMP-9, as well as an increase in apoptosis, in the parental/control lines. No significant additional inhibition in the viability and invasion of NFATc1-siRNA cells was seen. In xenograft-bearing mice, CsA and FK506 significantly retarded tumor growth. These results suggest that NFATc1 plays an important role in bladder cancer outgrowth. Thus, NFATc1 inactivation, especially using CsA and FK506, has the potential of being a therapeutic approach for bladder cancer.
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Affiliation(s)
- Takashi Kawahara
- Departments of Pathology and Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA
| | - Eiji Kashiwagi
- Departments of Pathology and Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Hiroki Ide
- Departments of Pathology and Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Yi Li
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA
| | - Yichun Zheng
- Departments of Pathology and Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA
| | - Yurina Miyamoto
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA
| | - George J. Netto
- Departments of Pathology and Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Hitoshi Ishiguro
- Departments of Pathology and Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA
| | - Hiroshi Miyamoto
- Departments of Pathology and Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA
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Kawahara T, Kashiwagi E, Li Y, Zheng Y, Miyamoto Y, Netto GJ, Ishiguro H, Miyamoto H. Cyclosporine A and tacrolimus inhibit urothelial tumorigenesis. Mol Carcinog 2015; 55:161-9. [DOI: 10.1002/mc.22265] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2014] [Revised: 11/06/2014] [Accepted: 11/26/2014] [Indexed: 01/20/2023]
Affiliation(s)
- Takashi Kawahara
- Departments of Pathology and Urology; Johns Hopkins University School of Medicine; Baltimore Maryland
- Department of Pathology and Laboratory Medicine; University of Rochester Medical Center; Rochester New York
| | - Eiji Kashiwagi
- Departments of Pathology and Urology; Johns Hopkins University School of Medicine; Baltimore Maryland
| | - Yi Li
- Department of Pathology and Laboratory Medicine; University of Rochester Medical Center; Rochester New York
| | - Yichun Zheng
- Departments of Pathology and Urology; Johns Hopkins University School of Medicine; Baltimore Maryland
- Department of Pathology and Laboratory Medicine; University of Rochester Medical Center; Rochester New York
| | - Yurina Miyamoto
- Department of Pathology and Laboratory Medicine; University of Rochester Medical Center; Rochester New York
| | - George J. Netto
- Departments of Pathology and Urology; Johns Hopkins University School of Medicine; Baltimore Maryland
| | - Hitoshi Ishiguro
- Departments of Pathology and Urology; Johns Hopkins University School of Medicine; Baltimore Maryland
- Department of Pathology and Laboratory Medicine; University of Rochester Medical Center; Rochester New York
| | - Hiroshi Miyamoto
- Departments of Pathology and Urology; Johns Hopkins University School of Medicine; Baltimore Maryland
- Department of Pathology and Laboratory Medicine; University of Rochester Medical Center; Rochester New York
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Cripto-1 expression and its prognostic value in human bladder cancer patients. Tumour Biol 2014; 36:1105-13. [DOI: 10.1007/s13277-014-2695-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2014] [Accepted: 09/30/2014] [Indexed: 11/25/2022] Open
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Ishiguro H, Kawahara T, Zheng Y, Netto GJ, Miyamoto H. Reduced glucocorticoid receptor expression predicts bladder tumor recurrence and progression. Am J Clin Pathol 2014; 142:157-64. [PMID: 25015855 DOI: 10.1309/ajcpu8ucezyg4wtv] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022] Open
Abstract
OBJECTIVES To assess the levels of glucocorticoid receptor (GR) expression in bladder tumors because the status and its prognostic value remain largely unknown. METHODS We immunohistochemically stained for GR in bladder tumor and matched non-neoplastic bladder tissue specimens. RESULTS Overall, GR was positive in 129 (87%) of 149 urothelial tumors, which was significantly (P=.026) lower than in non-neoplastic urothelium (90 [96%] of 94). Forty-two (79%) of 53 low-grade tumors vs 45 (47%) of 96 high-grade carcinomas (P<.001) and 61 (73%) of 84 non-muscle-invasive (NMI) tumors vs 26 (40%) of 65 muscle-invasive (MI) carcinomas (P<.001) were moderately to strongly immunoreactive for GR. Kaplan-Meier and log-rank tests revealed that loss or weak positivity of GR significantly or marginally correlated with recurrence of NMI tumors (P=.025), progression of MI tumors (P=.082), and cancer-specific survival of MI tumors (P=.067). Multivariate analysis identified low GR expression as a strong predictor for recurrence of NMI tumors (P=.034). CONCLUSIONS GR expression was downregulated in bladder tumors compared with nonneoplastic bladder tumors and in high-grade/MI tumors compared with low-grade/NMI tumors. Decreased expression of GR, as an independent prognosticator, predicted recurrence of NMI tumors. These results support experimental evidence suggesting an inhibitory role of GR signals in bladder cancer outgrowth.
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Affiliation(s)
- Hitoshi Ishiguro
- Departments of Pathology and Urology, The Johns Hopkins University School of Medicine, Baltimore, MD
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY
| | - Takashi Kawahara
- Departments of Pathology and Urology, The Johns Hopkins University School of Medicine, Baltimore, MD
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY
| | - Yichun Zheng
- Departments of Pathology and Urology, The Johns Hopkins University School of Medicine, Baltimore, MD
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY
| | - George J. Netto
- Departments of Pathology and Urology, The Johns Hopkins University School of Medicine, Baltimore, MD
| | - Hiroshi Miyamoto
- Departments of Pathology and Urology, The Johns Hopkins University School of Medicine, Baltimore, MD
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY
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Knapp DW, Ramos-Vara JA, Moore GE, Dhawan D, Bonney PL, Young KE. Urinary Bladder Cancer in Dogs, a Naturally Occurring Model for Cancer Biology and Drug Development. ILAR J 2014; 55:100-18. [DOI: 10.1093/ilar/ilu018] [Citation(s) in RCA: 150] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
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47
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Murphy CR, Karnes RJ. Bladder Cancer in Males: A Comprehensive Review of Urothelial Carcinoma of the Bladder. JOURNAL OF MEN'S HEALTH 2014. [DOI: 10.1089/jomh.2014.3503] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
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Abstract
Currently, bladder cancer ranks as the second most common genitourinary malignancy which is exacting significant morbidity and mortality worldwide. Although there are abundant epidemiological and basic studies which strongly suggest the role of androgen hormone in bladder cancer, the underlying mechanism is not fully understood. In the current study, we sought to identify a new competitive inhibitor for androgen receptor in bladder cancer cells. Our results showed that Nur77 hyperexpression inhibits UM-UC-3 cell growth and cell cycle progression while Nur77 knockdown exerts the opposite effect. In our cell culture model, we also demonstrated that Nur77 competitively inhibits androgen-dependent transcription activity and more specifically, Nur77 competes with androgen receptor for binding to src-1, a well-known coactivator for steroids. More importantly, we also showed that a small molecule agonist for Nur77, Cytosporone B, significantly inhibits androgen-dependent bladder cancer cell growth in two different cell lines. These data provide a good proof-of-principle that Nur77 signaling machinery could be a new target for growth control of androgen-dependent bladder cancer cells.
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Affiliation(s)
- Jianping Wu
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
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Li Y, Ishiguro H, Kawahara T, Kashiwagi E, Izumi K, Miyamoto H. Loss of GATA3 in bladder cancer promotes cell migration and invasion. Cancer Biol Ther 2014; 15:428-35. [PMID: 24448324 DOI: 10.4161/cbt.27631] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
The transcription factor GATA3 is known as a breast tumor suppressor as well as a urothelial marker, and its loss is often seen in high-grade invasive bladder cancer. Nonetheless, GATA3 functions in bladder cancer cells remain largely unknown. In this study, we assessed the effects of GATA3 silencing via RNA interference on cell migration, invasion, and proliferation of bladder cancer. GATA3 expression was downregulated in all four bladder cancer lines examined, compared with a non-neoplastic urothelial line SVHUC. Knockdown of GATA3 in the bladder cancer lines (5637, TCC-SUP, J82) resulted in promotion of cell migration and invasion as well as increases in the expression of their related molecules, such as vascular endothelial growth factor, matrix metalloproteinase (MMP)-2, and MMP-9, and the activity of MMP-2 and MMP-9. GATA3 loss was also associated with an increasing level of a mesenchymal marker N-cadherin and a decreasing level of an epithelial marker β-catenin. Consistent with these findings, enforced expression of GATA3 in UMUC3 inhibited cell migration and invasion. However, GATA3 showed marginal effects on bladder cancer cell viability and the expression of cell cycle- or apoptosis-related molecules. Additionally, in contrast to bladder cancer lines, no significant effects of GATA3 silencing on cell migration were seen in SVHUC. These findings suggest that GATA3 plays an important role in the prevention of bladder cancer progression and metastasis by inhibiting cell migration and invasion as well as epithelial-to-mesenchymal transition.
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Affiliation(s)
- Yi Li
- Department of Pathology and Laboratory Medicine; University of Rochester Medical Center; Rochester, NY USA; Department of Urology; 2nd Affiliated Hospital; Zhejiang University School of Medicine; Hangzhou, PR China
| | - Hitoshi Ishiguro
- Department of Pathology and Laboratory Medicine; University of Rochester Medical Center; Rochester, NY USA; Departments of Pathology and Urology; Johns hopkins University school of Medicine; Baltimore, MD UsA
| | - Takashi Kawahara
- Department of Pathology and Laboratory Medicine; University of Rochester Medical Center; Rochester, NY USA; Departments of Pathology and Urology; Johns hopkins University school of Medicine; Baltimore, MD UsA
| | - Eiji Kashiwagi
- Departments of Pathology and Urology; Johns hopkins University school of Medicine; Baltimore, MD UsA
| | - Koji Izumi
- Department of Pathology and Laboratory Medicine; University of Rochester Medical Center; Rochester, NY USA
| | - Hiroshi Miyamoto
- Department of Pathology and Laboratory Medicine; University of Rochester Medical Center; Rochester, NY USA; Departments of Pathology and Urology; Johns hopkins University school of Medicine; Baltimore, MD UsA
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Taylor CF, Platt FM, Hurst CD, Thygesen HH, Knowles MA. Frequent inactivating mutations of STAG2 in bladder cancer are associated with low tumour grade and stage and inversely related to chromosomal copy number changes. Hum Mol Genet 2013; 23:1964-74. [PMID: 24270882 PMCID: PMC3959811 DOI: 10.1093/hmg/ddt589] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Inactivating mutations of STAG2 have been reported at low frequency in several cancers. In glioblastoma, the function of STAG2 has been related to maintenance of euploidy via its role in the cohesin complex. In a screen of a large series of bladder tumours and cell lines, we found inactivating mutations (nonsense, frameshift and splicing) in 67 of 307 tumours (21.8%) and 6 of 47 cell lines. Thirteen missense mutations of unknown significance were also identified. Inactivating mutation was associated with low tumour stage (P = 0.001) and low grade (P = 0.0002). There was also a relationship with female patient gender (P = 0.042). Examination of copy number profiles revealed an inverse relationship of mutation with both fraction of genome altered and whole chromosome copy number changes. Immunohistochemistry showed that in the majority of cases with inactivating mutations, STAG2 protein expression was absent. Strikingly, we identified a relatively large subset of tumours (12%) with areas of both positive and negative immunoreactivity, in only four of which a potentially function-altering mutation was detected. Regions of differential expression were contiguous and showed similar morphological phenotype in all cases. Microdissected positive and negative areas from one tumour showed an inactivating mutation to be present only in the negative area, suggesting intra-tumoral sub-clonal genomic evolution. Our findings indicate that loss of STAG2 function plays a more important role in non-invasive than that in muscle-invasive bladder cancer and suggest that cohesin complex-independent functions are likely to be important in these cases.
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