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Zhao J, Zhang Q, Zhu C, Yuqi W, Zhang G, Wang Q, Dong X, Li B, Wang X. Prognostic feature based on androgen-responsive genes in bladder cancer and screening for potential targeted drugs. BioData Min 2024; 17:59. [PMID: 39695796 DOI: 10.1186/s13040-024-00377-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Accepted: 07/19/2024] [Indexed: 12/20/2024] Open
Abstract
OBJECTIVES Bladder cancer (BLCA) is a tumor that affects men more than women. The biological function and prognostic value of androgen-responsive genes (ARGs) in BLCA are currently unknown. To address this, we established an androgen signature to determine the prognosis of BLCA. METHODS Sequencing data for BLCA from the TCGA and GEO datasets were used for research. The tumor microenvironment (TME) was measured using Cibersort and ssGSEA. Prognosis-related genes were identified and a risk score model was constructed using univariate Cox regression, LASSO regression, and multivariate Cox regression. Drug sensitivity analysis was performed using Genomics of drug sensitivity in cancer (GDSC). Real-time quantitative PCR was performed to assess the expression of representative genes in clinical samples. RESULTS ARGs (especially the CDK6, FADS1, PGM3, SCD, PTK2B, and TPD52) might regulate the progression of BLCA. The different expression patterns of ARGs may lead to different immune cell infiltration. The risk model indicates that patients with higher risk scores have a poorer prognosis, more stromal infiltration, and an enrichment of biological functions. Single-cell RNA analysis, bulk RNA data, and PCR analysis support the reliability of this risk model, and a nomogram was also established for clinical use. Drug prediction analysis showed that high-risk patients had a better response to fludarabine, AZD8186, and carmustine. CONCLUSION ARGs played an important role in the progression, immune infiltration, and prognosis of BLCA. The ARGs model has high accuracy in predicting the prognosis of BLCA patients and provides more effective medication guidelines.
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Affiliation(s)
- Jiang Zhao
- Department of Urology, Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-Communicable Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
- Department of Urology, Second Affiliated Hospital, Army Medical University, Chongqing, 400037, China
- Department of Urology, People ' s Hospital of Shapingba District, Chongqing, 400030, China
| | - Qian Zhang
- Department of Urology, General Hospital of Northern Theater Command, Shenyang, 110016, China
| | - Cunle Zhu
- Department of Urology, Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-Communicable Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Wu Yuqi
- Department of Urology, Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-Communicable Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
- Department of Urology, South China Hospital Affiliated to Shenzhen University, Shenzhen, 518000, China
| | - Guohui Zhang
- Department of Urology, Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-Communicable Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Qianliang Wang
- Department of Urology, Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-Communicable Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Xingyou Dong
- Department of Urology, South China Hospital Affiliated to Shenzhen University, Shenzhen, 518000, China.
- Department of Urology, People ' s Hospital of Shapingba District, Chongqing, 400030, China.
| | - Benyi Li
- Department of Urology, The University of Kansas Medical Center, Kansas City, KS, 66160, USA.
| | - Xiangwei Wang
- Department of Urology, Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-Communicable Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China.
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Goto T, Teramoto Y, Nagata Y, Miyamoto H. Latrophilin-3 as a downstream effector of the androgen receptor induces bladder cancer progression. Discov Oncol 2024; 15:440. [PMID: 39269616 PMCID: PMC11399515 DOI: 10.1007/s12672-024-01324-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Accepted: 09/06/2024] [Indexed: 09/15/2024] Open
Abstract
Emerging evidence indicates that androgen receptor (AR) signaling plays a critical role in the pathogenesis of male-dominant urothelial cancer and its outgrowth. Meanwhile, latrophilins (LPHNs), a group of the G-protein-coupled receptors to which a spider venom latrotoxin (LTX) is known to bind, remain largely uncharacterized in neoplastic diseases. The present study aimed to determine the functional role of LPHN3 (encoded by the ADGRL3 gene), in association with AR signaling, in the progression of bladder cancer. In AR-positive bladder cancer lines, dihydrotestosterone considerably increased the expression levels of ADGRL3 and LPHN3, while chromatin immunoprecipitation assay revealed the binding of AR to the promoter region of ADGRL3. Treatment with LPHN3 ligands (e.g. α-LTX, FLRT3) resulted in the induction of ADGRL3 expression, as well as cell viability, in bladder cancer lines. By contrast, LPHN3 knockdown via shRNA virus infection significantly reduced the viability and migration of these cells. Immunohistochemistry in transurethral resection specimens further showed a strong correlation between LPHN3 and AR expression. Moreover, LPHN3 positivity in muscle-invasive bladder tumors, as an independent prognosticator, was associated with a significantly higher risk of disease progression and disease-specific mortality following radical cystectomy. These findings suggest that LPHN3 functions as a downstream effector of AR and promotes the growth of bladder cancer.
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Affiliation(s)
- Takuro Goto
- Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
| | - Yuki Teramoto
- Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
| | - Yujiro Nagata
- Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
| | - Hiroshi Miyamoto
- Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA.
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA.
- Department of Urology, University of Rochester Medical Center, Rochester, NY, USA.
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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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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Zhao J, Wang Q, Tan AF, Loh CJL, Toh HC. Sex differences in cancer and immunotherapy outcomes: the role of androgen receptor. Front Immunol 2024; 15:1416941. [PMID: 38863718 PMCID: PMC11165033 DOI: 10.3389/fimmu.2024.1416941] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2024] [Accepted: 05/16/2024] [Indexed: 06/13/2024] Open
Abstract
Across the wide range of clinical conditions, there exists a sex imbalance where biological females are more prone to autoimmune diseases and males to some cancers. These discrepancies are the combinatory consequence of lifestyle and environmental factors such as smoking, alcohol consumption, obesity, and oncogenic viruses, as well as other intrinsic biological traits including sex chromosomes and sex hormones. While the emergence of immuno-oncology (I/O) has revolutionised cancer care, the efficacy across multiple cancers may be limited because of a complex, dynamic interplay between the tumour and its microenvironment (TME). Indeed, sex and gender can also influence the varying effectiveness of I/O. Androgen receptor (AR) plays an important role in tumorigenesis and in shaping the TME. Here, we lay out the epidemiological context of sex disparity in cancer and then review the current literature on how AR signalling contributes to such observation via altered tumour development and immunology. We offer insights into AR-mediated immunosuppressive mechanisms, with the hope of translating preclinical and clinical evidence in gender oncology into improved outcomes in personalised, I/O-based cancer care.
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Affiliation(s)
- Junzhe Zhao
- Duke-NUS Medical School, Singapore, Singapore
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | - Qian Wang
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
- Department of Medical Oncology Cancer Hospital of China Medical University/Liaoning Cancer Hospital & Institute, Shenyang, Liaoning, China
| | | | - Celestine Jia Ling Loh
- Duke-NUS Medical School, Singapore, Singapore
- Sengkang General Hospital, Singapore, Singapore
| | - Han Chong Toh
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
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Sundi D, Collier KA, Yang Y, Diaz DA, Pohar KS, Singer EA, Gupta S, Carson WE, Clinton SK, Li Z, Messing EM. Roles of Androgen Receptor Signaling in Urothelial Carcinoma. Cancers (Basel) 2024; 16:746. [PMID: 38398136 PMCID: PMC10886823 DOI: 10.3390/cancers16040746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Revised: 01/31/2024] [Accepted: 02/07/2024] [Indexed: 02/25/2024] Open
Abstract
Preclinical and clinical data suggest that androgen receptor signaling strongly contributes to bladder cancer development. The roles of the androgen receptor in bladder carcinogenesis have obvious implications for understanding the strong male sex bias in this disease and for potential therapeutic strategies as well. In this review, we summarize what is known about androgen receptor signaling in urothelial carcinoma as well as in tumor-infiltrating immune cells, reviewing preclinical and clinical data. We also highlight clinical trial efforts in this area.
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Affiliation(s)
- Debasish Sundi
- Department of Urology, Division of Urologic Oncology, Pelotonia Institute for Immuno-Oncology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Katharine A. Collier
- Department of Internal Medicine, Division of Medical Oncology, Pelotonia Institute for Immuno-Oncology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Yuanquan Yang
- Department of Internal Medicine, Division of Medical Oncology, Pelotonia Institute for Immuno-Oncology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Dayssy Alexandra Diaz
- Department of Radiation Oncology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Kamal S. Pohar
- Department of Urology, Division of Urologic Oncology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA (E.A.S.)
| | - Eric A. Singer
- Department of Urology, Division of Urologic Oncology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA (E.A.S.)
| | - Sanjay Gupta
- Department of Urology, Case Western Reserve University School of Medicine, The Urology Institute, University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA;
| | - William E. Carson
- Department of Surgery, Division of Surgical Oncology, Pelotonia Institute for Immuno-Oncology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Steven K. Clinton
- Department of Internal Medicine, Division of Medical Oncology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Zihai Li
- Department of Internal Medicine, Division of Medical Oncology, Pelotonia Institute for Immuno-Oncology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Edward M. Messing
- Departments of Urology, Oncology, and Pathology, University of Rochester Medical Center, Rochester, NY 14642, USA
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6
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Ramal M, Corral S, Kalisz M, Lapi E, Real FX. The urothelial gene regulatory network: understanding biology to improve bladder cancer management. Oncogene 2024; 43:1-21. [PMID: 37996699 DOI: 10.1038/s41388-023-02876-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Revised: 10/13/2023] [Accepted: 10/18/2023] [Indexed: 11/25/2023]
Abstract
The urothelium is a stratified epithelium composed of basal cells, one or more layers of intermediate cells, and an upper layer of differentiated umbrella cells. Most bladder cancers (BLCA) are urothelial carcinomas. Loss of urothelial lineage fidelity results in altered differentiation, highlighted by the taxonomic classification into basal and luminal tumors. There is a need to better understand the urothelial transcriptional networks. To systematically identify transcription factors (TFs) relevant for urothelial identity, we defined highly expressed TFs in normal human bladder using RNA-Seq data and inferred their genomic binding using ATAC-Seq data. To focus on epithelial TFs, we analyzed RNA-Seq data from patient-derived organoids recapitulating features of basal/luminal tumors. We classified TFs as "luminal-enriched", "basal-enriched" or "common" according to expression in organoids. We validated our classification by differential gene expression analysis in Luminal Papillary vs. Basal/Squamous tumors. Genomic analyses revealed well-known TFs associated with luminal (e.g., PPARG, GATA3, FOXA1) and basal (e.g., TP63, TFAP2) phenotypes and novel candidates to play a role in urothelial differentiation or BLCA (e.g., MECOM, TBX3). We also identified TF families (e.g., KLFs, AP1, circadian clock, sex hormone receptors) for which there is suggestive evidence of their involvement in urothelial differentiation and/or BLCA. Genomic alterations in these TFs are associated with BLCA. We uncover a TF network involved in urothelial cell identity and BLCA. We identify novel candidate TFs involved in differentiation and cancer that provide opportunities for a better understanding of the underlying biology and therapeutic intervention.
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Affiliation(s)
- Maria Ramal
- Epithelial Carcinogenesis Group, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Sonia Corral
- Epithelial Carcinogenesis Group, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Mark Kalisz
- Epithelial Carcinogenesis Group, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
- CIBERONC, Madrid, Spain
| | - Eleonora Lapi
- Epithelial Carcinogenesis Group, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
- CIBERONC, Madrid, Spain
| | - Francisco X Real
- Epithelial Carcinogenesis Group, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
- CIBERONC, Madrid, Spain.
- Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
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7
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Khalifa SE. Immunohistochemical expression of CD117/KIT, HER2, and Erβ in schistosomal and non-schistosomal urothelial carcinoma of Egyptian patients. Int Urol Nephrol 2023; 55:2473-2481. [PMID: 37338655 PMCID: PMC10499727 DOI: 10.1007/s11255-023-03667-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Accepted: 06/05/2023] [Indexed: 06/21/2023]
Abstract
Bladder carcinoma is an endemic problem in Egypt with schistosomiasis being an additional risk factor. Due to gender disparities, Erβ investigation and its role in modulating chemosensitivity are studied. CD117/KIT expression is also considered since the emergence of the targets of the tyrosine kinase inhibitor imatinib mesylate (Gleevec). HER2 is one of the established therapeutic targets in many cancers. We aimed to investigate CD117/KIT immunoexpression in schistosomal and non-schistosomal urothelial carcinoma of Egyptian patients and its relationship with HER2 and Erβ expressions, correlating it with pertinent variables that will help to provide better treatment options of possible combined targeted and hormonal therapy that might be effective against this aggressive malignancy. Sixty cases of bladder carcinoma were tested. Depending on the schistosomiasis association status of each case, two groups have been established with 30 cases each. CD117/KIT, HER2, and ERβ immunostaining were done and correlated with clinico- immuno-pathological parameters. CD117/KIT expression was seen in 71.7% of cases that correlated significantly with schistosomiasis (P = 0.01). In addition, a positive correlation was detected between schistosomiasis association and the percentage of immunostained cells and intensity score of CD117/KIT with P = 0.027, 0.01, respectively. 30% and 61.7% of cases were positively stained with HER2 and Erβ, respectively, with no significant relation with schistosomiasis. Due to the high expression, we found further clinical trials are needed to offer individualized targeted therapeutic options in urothelial tumors using anti-CD117/KIT, HER2, and ERβ other than limited traditional chemo- and nontargeted therapies.
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Affiliation(s)
- Sara E Khalifa
- Department of Pathology, Faculty of Medicine, Cairo University, Cairo, 11728, Egypt.
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Elahi Najafi MA, Yasui M, Teramoto Y, Tatenuma T, Jiang G, Miyamoto H. GABBR2 as a Downstream Effector of the Androgen Receptor Induces Cisplatin Resistance in Bladder Cancer. Int J Mol Sci 2023; 24:13733. [PMID: 37762034 PMCID: PMC10530579 DOI: 10.3390/ijms241813733] [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: 08/22/2023] [Revised: 08/29/2023] [Accepted: 09/05/2023] [Indexed: 09/29/2023] Open
Abstract
The precise molecular mechanisms responsible for resistance to cisplatin-based chemotherapy in patients with bladder cancer remain elusive, while we have indicated that androgen receptor (AR) activity in urothelial cancer is associated with its sensitivity. Our DNA microarray analysis in control vs. AR-knockdown bladder cancer sublines suggested that the expression of a GABA B receptor GABBR2 and AR was correlated. The present study aimed to determine the functional role of GABBR2 in modulating cisplatin sensitivity in bladder cancer. AR knockdown and dihydrotestosterone treatment considerably reduced and induced, respectively, GABBR2 expression, and the effect of dihydrotestosterone was at least partially restored by an antiandrogen hydroxyflutamide. A chromatin immunoprecipitation assay further revealed the binding of AR to the promoter region of GABBR2 in bladder cancer cells. Meanwhile, GABBR2 expression was significantly elevated in a cisplatin-resistant bladder cancer subline, compared with control cells. In AR-positive bladder cancer cells, knockdown of GABBR2 or treatment with a selective GABA B receptor antagonist, CGP46381, considerably enhanced the cytotoxic activity of cisplatin. However, no additional effect of CGP46381 on cisplatin-induced growth suppression was seen in GABBR2-knockdown cells. Moreover, in the absence of cisplatin, CGP46381 treatment and GABBR2 knockdown showed no significant changes in cell proliferation or migration. These findings suggest that GABBR2 represents a key downstream effector of AR signaling in inducing resistance to cisplatin treatment. Accordingly, inhibition of GABBR2 has the potential of being a means of chemosensitization, especially in patients with AR/GABBR2-positive bladder cancer.
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Affiliation(s)
- Mohammad Amin Elahi Najafi
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA; (M.A.E.N.); (M.Y.); (Y.T.); (T.T.); (G.J.)
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Masato Yasui
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA; (M.A.E.N.); (M.Y.); (Y.T.); (T.T.); (G.J.)
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Yuki Teramoto
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA; (M.A.E.N.); (M.Y.); (Y.T.); (T.T.); (G.J.)
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Tomoyuki Tatenuma
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA; (M.A.E.N.); (M.Y.); (Y.T.); (T.T.); (G.J.)
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Guiyang Jiang
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA; (M.A.E.N.); (M.Y.); (Y.T.); (T.T.); (G.J.)
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Hiroshi Miyamoto
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA; (M.A.E.N.); (M.Y.); (Y.T.); (T.T.); (G.J.)
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642, USA
- Department of Urology, University of Rochester Medical Center, Rochester, NY 14642, USA
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9
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Chen J, Huang CP, Quan C, Zu X, Ou Z, Tsai YC, Messing E, Yeh S, Chang C. The androgen receptor in bladder cancer. Nat Rev Urol 2023; 20:560-574. [PMID: 37072491 DOI: 10.1038/s41585-023-00761-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/10/2023] [Indexed: 04/20/2023]
Abstract
Bladder cancer is the ninth most common cancer worldwide with a striking sex-based difference in incidence. Emerging evidence indicates that the androgen receptor (AR) might promote the development, progression and recurrence of bladder cancer, contributing to the observed sex differences. Targeting androgen-AR signalling has promise as potential therapy for bladder cancer and helps to suppress progression of this disease. In addition, the identification of a new membrane AR and AR-regulated non-coding RNAs has important implications for bladder cancer treatment. The success of human clinical trials of targeted-AR therapies will help in the development of improved treatments for patients with bladder cancer.
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Affiliation(s)
- Jinbo Chen
- Department of Urology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- Departments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA
| | - Chi-Ping Huang
- Department of Urology, China Medical University Hospital, Taichung, Taiwan
| | - Chao Quan
- Department of Urology, Xiangya Hospital, Central South University, Changsha, China
| | - Xiongbing Zu
- Department of Urology, Xiangya Hospital, Central South University, Changsha, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
| | - Zhenyu Ou
- Department of Urology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- Departments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA
| | - Yu-Chieh Tsai
- Departments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA
| | - Edward Messing
- Departments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA
| | - Shuyuan Yeh
- Departments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA
| | - Chawnshang Chang
- Departments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA.
- Department of Urology, China Medical University Hospital, Taichung, Taiwan.
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10
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Leo J, Dondossola E, Basham KJ, Wilson NR, Alhalabi O, Gao J, Kurnit KC, White MG, McQuade JL, Westin SN, Wellberg EA, Frigo DE. Stranger Things: New Roles and Opportunities for Androgen Receptor in Oncology Beyond Prostate Cancer. Endocrinology 2023; 164:bqad071. [PMID: 37154098 PMCID: PMC10413436 DOI: 10.1210/endocr/bqad071] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 04/25/2023] [Accepted: 05/05/2023] [Indexed: 05/10/2023]
Abstract
The androgen receptor (AR) is one of the oldest therapeutic targets in oncology and continues to dominate the treatment landscape for advanced prostate cancer, where nearly all treatment regimens include some form of AR modulation. In this regard, AR remains the central driver of prostate cancer cell biology. Emerging preclinical and clinical data implicate key roles for AR in additional cancer types, thereby expanding the importance of this drug target beyond prostate cancer. In this mini-review, new roles for AR in other cancer types are discussed as well as their potential for treatment with AR-targeted agents. Our understanding of these additional functions for AR in oncology expand this receptor's potential as a therapeutic target and will help guide the development of new treatment approaches.
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Affiliation(s)
- Javier Leo
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
- The University of Texas MD Anderson Cancer Center, UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA
| | - Eleonora Dondossola
- Department of Genitourinary Medical Oncology and the David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Kaitlin J Basham
- Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA
| | - Nathaniel R Wilson
- Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Omar Alhalabi
- Department of Genitourinary Medical Oncology and the David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Jianjun Gao
- Department of Genitourinary Medical Oncology and the David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Katherine C Kurnit
- Department of Obstetrics and Gynecology, Section of Gynecologic Oncology, The University of Chicago, Chicago, IL 60637, USA
| | - Michael G White
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Jennifer L McQuade
- Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Shannon N Westin
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Elizabeth A Wellberg
- Department of Pathology, Harold Hamm Diabetes Center, and Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Daniel E Frigo
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
- Department of Genitourinary Medical Oncology and the David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX 77204, USA
- Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USA
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11
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Yasui M, Cui L, Miyamoto H. Recent advances in the understanding of urothelial tumorigenesis. Expert Rev Anticancer Ther 2023; 23:485-493. [PMID: 37052619 DOI: 10.1080/14737140.2023.2203388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/14/2023]
Abstract
INTRODUCTION Patients with non-muscle-invasive bladder tumor suffer from disease recurrence following transurethral surgery even with intravesical pharmacotherapy, while muscle-invasive disease is often deadly. It is therefore critical to elucidate the underlying molecular mechanisms responsible for not only bladder tumor progression but also its tumorigenesis. Indeed, various molecules and/or signaling pathways have been suggested to contribute to the pathogenesis of bladder cancer. AREAS COVERED We summarize the progress during the last few years on the initiation or development, but not progression, of urothelial cancer. The clinical implications of these available data, including prognostic significance and possible application for the prevention of the recurrence of non-muscle-invasive bladder tumors, are also discussed. EXPERT OPINION Bladder cancer is a heterogeneous group of neoplasms. The establishment of personalized therapeutic options based on the molecular profile in each case should thus be considered. On that account, further accumulation of data on urothelial tumorigenesis is warranted to identify promising targets for the prevention of postoperative tumor recurrence or tumor development in otherwise high-risk patients.
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Affiliation(s)
- Masato Yasui
- Department of Pathology & Laboratory Medicine, Rochester, NY, USA
- James P. Wilmot Cancer Institute, Rochester, NY, USA
| | - Liam Cui
- Department of Pathology & Laboratory Medicine, Rochester, NY, USA
| | - Hiroshi Miyamoto
- Department of Pathology & Laboratory Medicine, Rochester, NY, USA
- James P. Wilmot Cancer Institute, Rochester, NY, USA
- Department of Urology, University of Rochester Medical Center, Rochester, NY, USA
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12
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Sun A, Luo Y, Xiao W, Zhu Z, Yan H, Miao C, Zhang W, Bai P, Liu C, Yang D, Shao Z, Song J, Wu Z, Chen B, Xing J, Wang T. Androgen receptor transcriptionally inhibits programmed death ligand-1 (PD-L1) expression and influences immune escape in bladder cancer. J Transl Med 2023; 103:100148. [PMID: 37059268 DOI: 10.1016/j.labinv.2023.100148] [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: 12/19/2022] [Revised: 03/14/2023] [Accepted: 04/04/2023] [Indexed: 04/16/2023] Open
Abstract
In multiple clinical trials, immune checkpoint blockade-based immunotherapy has shown significant therapeutic efficacy in bladder cancer (BCa). Sex is closely related to the incidence rate and prognosis of BCa. As one of the sex hormone receptors, the androgen receptor (AR) is a well-known key regulator that promotes the progression of BCa. However, the regulatory mechanism of AR in the immune response of BCa is still unclear. In this study, the expression of AR and programmed cell death-ligand 1 (PD-L1) was negatively correlated in BCa cells, clinical tissues, and tumor data extracted from The Cancer Genome Atlas Bladder Urothelial Carcinoma (TCGA-BLCA) cohort. A human BCa cell line was transfected to alter expression of AR. The results show that AR negatively regulated PD-L1 expression by directly binding to AR response elements (AREs) on the PD-L1 promoter region. In addition, AR overexpression in BCa cells significantly enhanced the antitumor activity of co-cultured CD8+ T cells. Injection of anti-PD-L1 monoclonal antibodies into C3H/HeN mice significantly suppressed tumor growth, and stable expression of AR dramatically enhanced the antitumor activity in vivo. In conclusion, this study describes a novel role of AR in regulating the immune response to BCa by targeting PD-L1, thus providing potential therapeutic strategies for immunotherapy in BCa.
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Affiliation(s)
- Anran Sun
- The Key Laboratory of Urinary Tract Tumors and Calculi, Department of Urology Surgery, The First Affiliated Hospital, School of Medicine, Xiamen University, Xiamen, China; Oncology Research Center, Foresea Life Insurance Guangzhou General Hospital, Guangzhou, Guangdong, China
| | - Yu Luo
- The Key Laboratory of Urinary Tract Tumors and Calculi, Department of Urology Surgery, The First Affiliated Hospital, School of Medicine, Xiamen University, Xiamen, China
| | - Wen Xiao
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhipeng Zhu
- School of Medicine, Xiamen University, Xiang'an, Xiamen, China
| | - Hongyu Yan
- School of Medicine, Xiamen University, Xiang'an, Xiamen, China
| | - Chaohao Miao
- The Key Laboratory of Urinary Tract Tumors and Calculi, Department of Urology Surgery, The First Affiliated Hospital, School of Medicine, Xiamen University, Xiamen, China
| | - Wenzhao Zhang
- The School of Clinical Medicine, Fujian Medical University, Fuzhou, China
| | - Peide Bai
- The Key Laboratory of Urinary Tract Tumors and Calculi, Department of Urology Surgery, The First Affiliated Hospital, School of Medicine, Xiamen University, Xiamen, China
| | - Chenfeng Liu
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiang'an, Xiamen, China
| | - Dianqiang Yang
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiang'an, Xiamen, China
| | - Zhiqiang Shao
- Xiamen University Laboratory Animal Center, Xiamen University, Xiang'an, Xiamen, China
| | - Jing Song
- Xiamen University Laboratory Animal Center, Xiamen University, Xiang'an, Xiamen, China
| | - Zhun Wu
- The Key Laboratory of Urinary Tract Tumors and Calculi, Department of Urology Surgery, The First Affiliated Hospital, School of Medicine, Xiamen University, Xiamen, China
| | - Bin Chen
- The Key Laboratory of Urinary Tract Tumors and Calculi, Department of Urology Surgery, The First Affiliated Hospital, School of Medicine, Xiamen University, Xiamen, China; The School of Clinical Medicine, Fujian Medical University, Fuzhou, China.
| | - Jinchun Xing
- The Key Laboratory of Urinary Tract Tumors and Calculi, Department of Urology Surgery, The First Affiliated Hospital, School of Medicine, Xiamen University, Xiamen, China; The School of Clinical Medicine, Fujian Medical University, Fuzhou, China.
| | - Tao Wang
- The Key Laboratory of Urinary Tract Tumors and Calculi, Department of Urology Surgery, The First Affiliated Hospital, School of Medicine, Xiamen University, Xiamen, China; The School of Clinical Medicine, Fujian Medical University, Fuzhou, China.
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13
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Garg H, Wheeler KM, Dursun F, Cooper RE, Pruthi DK, Kaushik D, Thompson IM, Svatek RS, Liss MA. Impact of Finasteride on survival in bladder cancer: A retrospective multi-institutional database analysis. Clin Genitourin Cancer 2022; 21:314.e1-314.e7. [PMID: 36402643 DOI: 10.1016/j.clgc.2022.10.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 10/16/2022] [Accepted: 10/24/2022] [Indexed: 11/18/2022]
Abstract
INTRODUCTION Androgen suppression therapy has been associated with a lower incidence of bladder cancer (BCa) or improved overall/cancer-specific survival. Results are ofent conflicting; therefore, we aim to assess the impact of use of finasteride on overall survival (OS) for BCa using multi-institutional database. METHODS The South Texas Veterans Healthcare System from 5 medical centers was queried for patients with BCa with or without use of finasteride after diagnosis of BCa. The primary outcome was the impact of finasteride use after diagnosis on the OS in BCa and in the high-risk Non-muscle invasive BCa (NMIBC) cohort. RESULTS A total of 1890 patients were included, amongst which 619 (32.8%) men were classified as finasteride users and 1271 (67.2%) men as controls. At a median (IQR) follow up of 53.8 (27.4, 90.9) months, death due to any cause was noted in 272 (43.9%) finasteride-treated, and 672 (49.3%) control groups (P = .028). The patients in the finasteride group had significantly better OS in overall cohort (112.1 months vs. 84.8 months, P < .001) as well as in the NMIBC cohort (129.3months vs. 103.2 months, P = .0046). The use of finasteride was independently associated with improved OS in both, overall cohort (HR 0.74, 95% CI 0.63-0.86; P < .001) and in the NMIBC cohort (HR = 0.71, 95% CI 0.55-0.93; P = .011). CONCLUSION Finasteride use is associated with the improved overall survival in patients with BCa, specifically in patients with NMIBC. We, further, propose a randomized clinical trial to investigate the use of finasteride in BCa patients.
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Affiliation(s)
- Harshit Garg
- Department of Urology, University of Texas Health, San Antonio, TX
| | - Karen M Wheeler
- Department of Urology, University of Texas Health, San Antonio, TX
| | - Furkan Dursun
- Department of Urology, University of Texas Health, San Antonio, TX
| | - Robert E Cooper
- Department of Urology, University of Texas Health, San Antonio, TX
| | - Deepak K Pruthi
- Department of Urology, University of Texas Health, San Antonio, TX
| | - Dharam Kaushik
- Department of Urology, University of Texas Health, San Antonio, TX
| | | | - Robert S Svatek
- Department of Urology, University of Texas Health, San Antonio, TX
| | - Michael A Liss
- Department of Urology, University of Texas Health, San Antonio, TX; South Texas Veterans Healthcare System, San Antonio, TX.
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14
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De Carlo C, Valeri M, Corbitt DN, Cieri M, Colombo P. Non-muscle invasive bladder cancer biomarkers beyond morphology. Front Oncol 2022; 12:947446. [PMID: 35992775 PMCID: PMC9382689 DOI: 10.3389/fonc.2022.947446] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Accepted: 07/11/2022] [Indexed: 11/13/2022] Open
Abstract
Non-muscle invasive bladder cancer (NMIBC) still represents a challenge in decision-making and clinical management since prognostic and predictive biomarkers of response to treatment are still under investigation. In addition to the risk factors defined by EORTC guidelines, histological features have also been considered key variables able to impact on recurrence and progression in bladder cancer. Conversely, the role of genomic rearrangements or expression of specific proteins at tissue level need further assessment in NMIBC. As with muscle-invasive cancer, NMIBC is a heterogeneous disease, characterized by genomic instability, varying rates of mutation and a wide range of protein tissue expression. In this Review, we summarized the recent evidence on prognostic and predictive tissue biomarkers in NMIBC, beyond morphological parameters, outlining how they could affect tumor biology and consequently its behavior during clinical care. Our aim was to facilitate clinical evaluation of promising biomarkers that may be employed to better stratify patients. We described the most common molecular events and immunohistochemical protein expressions linked to recurrence and progression. Moreover, we discussed the link between available treatments and molecular drivers that could be predictive of clinical response. In conclusion, we foster further investigations with particular focus on immunohistochemical evaluation of tissue biomarkers, a promising and cost-effective tool for daily practice.
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Affiliation(s)
- Camilla De Carlo
- Department of Pathology, IRCCS Humanitas Research Hospital, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Marina Valeri
- Department of Pathology, IRCCS Humanitas Research Hospital, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | | | - Miriam Cieri
- Department of Pathology, IRCCS Humanitas Research Hospital, Milan, Italy
| | - Piergiuseppe Colombo
- Department of Pathology, IRCCS Humanitas Research Hospital, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
- *Correspondence: Piergiuseppe Colombo,
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15
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Muzaail HH, El-Assmy A, Harraz AM, Awadalla A, Shokeir AA, Abdel-Aziz AF. Prediction of recurrence of non-muscle invasive bladder cancer: The role of androgen receptor and miRNA-2909. Urol Oncol 2022; 40:197.e25-197.e35. [PMID: 35430138 DOI: 10.1016/j.urolonc.2022.03.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 03/07/2022] [Accepted: 03/10/2022] [Indexed: 10/18/2022]
Abstract
AIM The exact role of androgen receptor (AR) and miR-2909 in non-muscle invasive bladder cancer (NMIBC) remains controversial. Our aim is to assess the relationship between NMIBC recurrences with AR expression and miRNA-2909. PATIENTS AND METHODS This prospective controlled cohort study included 99 male patients with NMIBC (Ta-T1) who were treated by transurethral resection and 50 male patients as healthy control. We quantified blood AR messenger RNA variants 1 and 2 (AR1, AR2) and plasma miRNA-2909 with real-time quantitative polymerase chain reaction and the full length AR (AR-FL) using enzyme-linked immunosorbent assay in serum samples. In addition, AR1 and AR2 expression in tumor as well as normal tissues were analyzed. Kaplan-Meier survival curves and multivariate Cox analysis were used to identify independent predictors of recurrence-free survival. RESULTS In comparison to control group, blood AR1, AR2, and serum AR-FL expression were significantly lower in the NMIBC group compared to plasma miRNA-2909 expression that was significantly higher in the control group. Blood AR1, AR2, and serum AR-FL were significantly correlated with higher tumor stage (pT1) while plasma miRNA-2909 was not. The median survival time (months) was significantly better for higher blood AR1 (34 vs. 21; P = 0.03), lower plasma miRNA-2909 (29 vs. 8; P <0.001), lower AR2 in normal tissues (32 vs. 22; P = 0.007). On multivariate analysis, serum free testosterone (hazards ratio [HR]: 8.9; 95% CI: 1.8-45.1; P = 0.008), serum AR1 (HR: 0.5; 95% CI: 0.3-0.9; P = 0.02), and plasma miRNA-2909 (HR: 5.8; 95% CI: 2.3-14.7; P = 0.0002), and tissue AR2 (HR: 2.6; 95% CI: 1.4-4.7; P = 0.002) were independent predictor for NMIBC recurrence. CONCLUSIONS Blood and tissue levels of AR expression have a potential significant effect on NMIBC recurrence. Further studies are recommended to establish its exact role.
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Affiliation(s)
- Hazim Hadi Muzaail
- Department of Chemistry, Faculty of Science, Mansoura University, Mansoura, Egypt
| | - Ahmed El-Assmy
- Urology and Nephrology Center, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
| | - Ahmed M Harraz
- Urology and Nephrology Center, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Amira Awadalla
- Center of Excellence for Genome and Cancer Research, Urology and Nephrology Center, Mansoura University, Mansoura, Egypt
| | - Ahmed A Shokeir
- Center of Excellence for Genome and Cancer Research, Urology and Nephrology Center, Mansoura University, Mansoura, Egypt
| | - A F Abdel-Aziz
- Department of Chemistry, Faculty of Science, Mansoura University, Mansoura, Egypt
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16
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Xu J, Yu X, Ye H, Gao S, Deng N, Lu Y, Lin H, Zhang Y, Lu D. Comparative Metabolomics and Proteomics Reveal Vibrio parahaemolyticus Targets Hypoxia-Related Signaling Pathways of Takifugu obscurus. Front Immunol 2022; 12:825358. [PMID: 35095928 PMCID: PMC8793131 DOI: 10.3389/fimmu.2021.825358] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 12/23/2021] [Indexed: 12/14/2022] Open
Abstract
Coronavirus disease 2019 (COVID-19) raises the issue of how hypoxia destroys normal physiological function and host immunity against pathogens. However, there are few or no comprehensive omics studies on this effect. From an evolutionary perspective, animals living in complex and changeable marine environments might develop signaling pathways to address bacterial threats under hypoxia. In this study, the ancient genomic model animal Takifugu obscurus and widespread Vibrio parahaemolyticus were utilized to study the effect. T. obscurus was challenged by V. parahaemolyticus or (and) exposed to hypoxia. The effects of hypoxia and infection were identified, and a theoretical model of the host critical signaling pathway in response to hypoxia and infection was defined by methods of comparative metabolomics and proteomics on the entire liver. The changing trends of some differential metabolites and proteins under hypoxia, infection or double stressors were consistent. The model includes transforming growth factor-β1 (TGF-β1), hypoxia-inducible factor-1α (HIF-1α), and epidermal growth factor (EGF) signaling pathways, and the consistent changing trends indicated that the host liver tended toward cell proliferation. Hypoxia and infection caused tissue damage and fibrosis in the portal area of the liver, which may be related to TGF-β1 signal transduction. We propose that LRG (leucine-rich alpha-2-glycoprotein) is widely involved in the transition of the TGF-β1/Smad signaling pathway in response to hypoxia and pathogenic infection in vertebrates as a conserved molecule.
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Affiliation(s)
- Jiachang Xu
- State Key Laboratory of Biocontrol and School of Life Sciences, Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Guangdong Provincial Key Laboratory for Aquatic Economic Animals and Guangdong Provincial Engineering Technology Research Center for Healthy Breeding of Important Economic Fish, Sun Yat-Sen University, Guangzhou, China
| | - Xue Yu
- State Key Laboratory of Biocontrol and School of Life Sciences, Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Guangdong Provincial Key Laboratory for Aquatic Economic Animals and Guangdong Provincial Engineering Technology Research Center for Healthy Breeding of Important Economic Fish, Sun Yat-Sen University, Guangzhou, China
| | - Hangyu Ye
- State Key Laboratory of Biocontrol and School of Life Sciences, Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Guangdong Provincial Key Laboratory for Aquatic Economic Animals and Guangdong Provincial Engineering Technology Research Center for Healthy Breeding of Important Economic Fish, Sun Yat-Sen University, Guangzhou, China
| | - Songze Gao
- State Key Laboratory of Biocontrol and School of Life Sciences, Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Guangdong Provincial Key Laboratory for Aquatic Economic Animals and Guangdong Provincial Engineering Technology Research Center for Healthy Breeding of Important Economic Fish, Sun Yat-Sen University, Guangzhou, China
| | - Niuniu Deng
- State Key Laboratory of Biocontrol and School of Life Sciences, Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Guangdong Provincial Key Laboratory for Aquatic Economic Animals and Guangdong Provincial Engineering Technology Research Center for Healthy Breeding of Important Economic Fish, Sun Yat-Sen University, Guangzhou, China
| | - Yuyou Lu
- State Key Laboratory of Biocontrol and School of Life Sciences, Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Guangdong Provincial Key Laboratory for Aquatic Economic Animals and Guangdong Provincial Engineering Technology Research Center for Healthy Breeding of Important Economic Fish, Sun Yat-Sen University, Guangzhou, China
| | - Haoran Lin
- State Key Laboratory of Biocontrol and School of Life Sciences, Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Guangdong Provincial Key Laboratory for Aquatic Economic Animals and Guangdong Provincial Engineering Technology Research Center for Healthy Breeding of Important Economic Fish, Sun Yat-Sen University, Guangzhou, China.,Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China.,College of Ocean, Hainan University, Haikou, China
| | - Yong Zhang
- State Key Laboratory of Biocontrol and School of Life Sciences, Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Guangdong Provincial Key Laboratory for Aquatic Economic Animals and Guangdong Provincial Engineering Technology Research Center for Healthy Breeding of Important Economic Fish, Sun Yat-Sen University, Guangzhou, China
| | - Danqi Lu
- State Key Laboratory of Biocontrol and School of Life Sciences, Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Guangdong Provincial Key Laboratory for Aquatic Economic Animals and Guangdong Provincial Engineering Technology Research Center for Healthy Breeding of Important Economic Fish, Sun Yat-Sen University, Guangzhou, China
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17
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Xiao L, Sun W, Su Y, Lu N, He Y, Sheng X, Qi X, Xing K, Guo Y, Chang D, Wang X, Zhao J, Ni H. Dihydrotestosterone regulation of cyclooxygenase-2 expression in bovine endometrial epithelium cells by androgen receptor mediated EGFR/PI3K/Akt pathway. J Steroid Biochem Mol Biol 2021; 214:106001. [PMID: 34547381 DOI: 10.1016/j.jsbmb.2021.106001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 09/07/2021] [Accepted: 09/15/2021] [Indexed: 11/29/2022]
Abstract
Uterine prostaglandins F2α (PGF2α) is essential for implantation, initiation of luteolysis and delivery. Previous studies have demonstrated that the expression of Cyclooxygenase-2 (COX-2), an enzyme limiting PGF2α rate, is regulated by steroid hormones, and also dihydrotestosterone (DHT) may be involved in regulating COX-2 expression both positively and negatively. However, it remains unclear how whether DHT regulates COX-2 expression and consequent PGF2α release in bovine endometrial epithelial cells (EECs). In this study, we evaluated the localization of the two isoforms of DHT synthetase 5α-reductase (5α-red1 and 5α-red2) and androgen receptor (AR) in bovine endometria by immunohistochemistry, and investigated 5α-red1, 5α-red2, AR, and DHT levels at the different stages of endometria (follicle, early-, mid-, and late-pregnancy phases). The results showed that 5α-red1, 5α-red2 and AR all were expressed in endometria, and their expressions and the level of DHT significantly increased in the late-pregnancy phase compared with the mid-pregnancy phase. Moreover, we cultured EECs from the mid-pregnancy phase and the in vitro study showed that DHT dose-dependently increased COX-2 expression and PGF2a release, but AR antagonist (flutamide) inhibited the stimulating effect via DHT. In addition, the DHT-induced COX-2 expression and PGF2α release were subjected to the regulation of both EGFR/PI3K/Akt/NFkB signaling as the inhibitors of EGFR (AG1478) and PI3K/Akt (LY294002) and NFkB (QNZ) attenuated the DHT mediated effect. Taken together, the results demonstrated that DHT-induced COX-2 expression and consequent PGF2α release in bovine EECs were mediated through AR-derived EGFR transactivation and PI3K/Akt cascade leading to NFkB activation.
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Affiliation(s)
- Longfei Xiao
- Animal Science and Technology College, Beijing University of Agriculture, Beijing, China
| | - Wanxu Sun
- Animal Science and Technology College, Beijing University of Agriculture, Beijing, China
| | - Yue Su
- Animal Science and Technology College, Beijing University of Agriculture, Beijing, China
| | - Ning Lu
- Animal Science and Technology College, Beijing University of Agriculture, Beijing, China
| | - Yanan He
- Zhangjiagang Agriculture and Rural Affairs Bureau, Jiangsu, China
| | - Xihui Sheng
- Animal Science and Technology College, Beijing University of Agriculture, Beijing, China
| | - Xiaolong Qi
- Animal Science and Technology College, Beijing University of Agriculture, Beijing, China
| | - Kai Xing
- Animal Science and Technology College, Beijing University of Agriculture, Beijing, China
| | - Yong Guo
- Animal Science and Technology College, Beijing University of Agriculture, Beijing, China
| | - Di Chang
- Animal Science and Technology College, Beijing University of Agriculture, Beijing, China
| | - Xiangguo Wang
- Animal Science and Technology College, Beijing University of Agriculture, Beijing, China.
| | - Junjin Zhao
- National Grazing Headquarter, Beijing, China
| | - Hemin Ni
- Animal Science and Technology College, Beijing University of Agriculture, Beijing, China.
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18
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Androgen Receptor Signaling Induces Cisplatin Resistance via Down-Regulating GULP1 Expression in Bladder Cancer. Int J Mol Sci 2021; 22:ijms221810030. [PMID: 34576193 PMCID: PMC8466436 DOI: 10.3390/ijms221810030] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 09/08/2021] [Accepted: 09/13/2021] [Indexed: 12/20/2022] Open
Abstract
The underlying molecular mechanisms of resistance to cisplatin-based systemic chemotherapy in bladder cancer patients remain to be elucidated, while the link between androgen receptor (AR) activity and chemosensitivity in urothelial cancer has been implicated. Our DNA microarray analysis in control vs. AR knockdown bladder cancer lines identified GULP1 as a potential target of AR signaling. We herein determined the relationship between AR activity and GULP1 expression in bladder cancer cells and then assessed the functional role of GULP1 in cisplatin sensitivity. Androgen treatment in AR-positive cells or AR overexpression in AR-negative cells considerably reduced the levels of GULP1 expression. Chromatin immunoprecipitation further showed direct interaction of AR with the promoter region of GULP1. Meanwhile, GULP1 knockdown sublines were significantly more resistant to cisplatin treatment compared with respective controls. GULP1 knockdown also resulted in a significant decrease in apoptosis, as well as a significant increase in G2/M phases, when treated with cisplatin. In addition, GULP1 was immunoreactive in 74% of muscle-invasive bladder cancers from patients who had subsequently undergone neoadjuvant chemotherapy, including 53% of responders showing moderate (2+)/strong (3+) expression vs. 23% of non-responders showing 2+/3+ expression (P = 0.044). These findings indicate that GULP1 represents a key downstream effector of AR signaling in enhancing sensitivity to cisplatin treatment.
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19
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Gan K, Gao Y, Liu K, Xu B, Qin W. The Clinical Significance and Prognostic Value of HER2 Expression in Bladder Cancer: A Meta-Analysis and a Bioinformatic Analysis. Front Oncol 2021; 11:653491. [PMID: 34540657 PMCID: PMC8440975 DOI: 10.3389/fonc.2021.653491] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Accepted: 08/12/2021] [Indexed: 01/29/2023] Open
Abstract
OBJECTIVE Human Epidermal Growth Factor Receptor 2 (HER2) is highly expressed in multiple malignancies and associated with patients' prognosis, but its role in bladder cancer (BCa) remains elusive. We conducted this meta-analysis to explore the clinical significance and prognostic value of HER2 in BCa. METHODS PubMed was searched for studies published between January 1, 2000 and January 1, 2020. The odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (95%CIs) were used to investigate the relationship between HER2 and BCa pathological features. TCGA was mined for the information regarding as well. RESULTS Our study included 14 articles enrolling 1398 people. Expression of HER2 is higher in bladder cancer than in normal tissues. HER2 over-expression is associated with CIS, multifocal tumor, large tumor size, high tumor stage and grade, lymph node metastasis, progression, recurrence and papillary tumor. We could not find a significant association between HER2 expression and survival time in BCa patients. CONCLUSIONS Our meta and bioinformatic analysis indicated that HER2 expression was related to pathological malignancy and poor prognosis in BCa.
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Affiliation(s)
- Kai Gan
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi’an, China
| | - Yue Gao
- Surgical Research Center, Institute of Urology, Medical School of Southeast University, Nanjing, China
| | - Kuangzheng Liu
- Surgical Research Center, Institute of Urology, Medical School of Southeast University, Nanjing, China
| | - Bin Xu
- Surgical Research Center, Institute of Urology, Medical School of Southeast University, Nanjing, China
| | - Weijun Qin
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi’an, China
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20
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Sikic D, Eckstein M, Weyerer V, Kubon J, Breyer J, Roghmann F, Kunath F, Keck B, Erben P, Hartmann A, Wirtz RM, Wullich B, Taubert H, Wach S. High expression of ERBB2 is an independent risk factor for reduced recurrence-free survival in patients with stage T1 non-muscle-invasive bladder cancer. Urol Oncol 2021; 40:63.e9-63.e18. [PMID: 34330652 DOI: 10.1016/j.urolonc.2021.06.021] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 06/13/2021] [Accepted: 06/25/2021] [Indexed: 01/23/2023]
Abstract
INTRODUCTION Molecular markers associated with breast cancer are assumed to be associated with outcome in non-muscle-invasive bladder cancer (NMIBC). MATERIALS AND METHODS We retrospectively investigated the association of the mRNA expression of estrogen receptor 1 (ESR1) and 2 (ESR2), progesterone receptor (PGR), MKI67, and HER2 (ERBB2) with recurrence-free (RFS), cancer-specific (CSS), and overall survival (OS) in 80 patients with stage T1 NMIBC. RESULTS High expression of ESR2 (P = 0.003), ERBB2 (P < 0.001), and MKI67 (P = 0.029) was associated with shorter RFS. Only high ERBB2 was an independent prognostic factor for reduced RFS (HR = 2.98; P = 0.009). When sub stratifying the cohort, high ESR2 was associated with reduced RFS (P < 0.001), CSS (P = 0.037) and OS (P = 0.006) in patients without instillation therapy. High ESR2 was associated with reduced CSS (P = 0.018) and OS (P = 0.029) in females and with shorter RFS in both sexes (males: P = 0.035; females: P = 0.010). Patients with high ERBB2 showed reduced CSS (P = 0.011) and OS (P = 0.042) in females and reduced CSS (P = 0.012) in those without instillation, while RFS was significantly reduced irrespective of sex or instillation. CONCLUSION High mRNA expression of ERBB2 is an independent predictor of reduced RFS in patients with stage T1 NMIBC. High ERBB2 and ESR2 are associated with reduced outcomes, especially in females and patients without instillation therapy.
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Affiliation(s)
- Danijel Sikic
- Department of Urology and Pediatric Urology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany; Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany.
| | - Markus Eckstein
- Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany; Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Veronika Weyerer
- Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany; Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Jennifer Kubon
- Department of Urology and Pediatric Urology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany; Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany
| | - Johannes Breyer
- Department of Urology, University of Regensburg, Caritas St. Josef Medical Center, Regensburg, Germany
| | - Florian Roghmann
- Department of Urology, Marien Hospital Herne, Ruhr University Bochum, Herne, Germany
| | - Frank Kunath
- Department of Urology and Pediatric Urology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany; Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany
| | - Bastian Keck
- Department of Urology and Pediatric Urology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany; Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany
| | - Philipp Erben
- Department of Urology, University Medical Centre Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Arndt Hartmann
- Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany; Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Ralph M Wirtz
- STRATIFYER Molecular Pathology GmbH, Cologne, Germany
| | - Bernd Wullich
- Department of Urology and Pediatric Urology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany; Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany
| | - Helge Taubert
- Department of Urology and Pediatric Urology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany; Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany
| | - Sven Wach
- Department of Urology and Pediatric Urology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany; Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany
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21
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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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22
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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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Ide H, Miyamoto H. Sex Hormone Receptor Signaling in Bladder Cancer: A Potential Target for Enhancing the Efficacy of Conventional Non-Surgical Therapy. Cells 2021; 10:1169. [PMID: 34064926 PMCID: PMC8150801 DOI: 10.3390/cells10051169] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 05/03/2021] [Accepted: 05/06/2021] [Indexed: 12/12/2022] Open
Abstract
There have been critical problems in the non-surgical treatment for bladder cancer, especially residence to intravesical pharmacotherapy, including BCG immunotherapy, cisplatin-based chemotherapy, and radiotherapy. Recent preclinical and clinical evidence has suggested a vital role of sex steroid hormone-mediated signaling in the progression of urothelial cancer. Moreover, activation of the androgen receptor and estrogen receptor pathways has been implicated in modulating sensitivity to conventional non-surgical therapy for bladder cancer. This may indicate the possibility of anti-androgenic and anti-estrogenic drugs, apart from their direct anti-tumor activity, to function as sensitizers of such conventional treatment. This article summarizes available data suggesting the involvement of sex hormone receptors, such as androgen receptor, estrogen receptor-α, and estrogen receptor-β, in the progression of urothelial cancer, focusing on their modulation for the efficacy of conventional therapy, and discusses their potential of overcoming therapeutic resistance.
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Affiliation(s)
- Hiroki Ide
- Department of Urology, Keio University School of Medicine, Tokyo 160-8582, Japan;
| | - Hiroshi Miyamoto
- Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA
- Department of Urology, University of Rochester Medical Center, Rochester, NY 14642, USA
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642, USA
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24
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Identification of BXDC2 as a Key Downstream Effector of the Androgen Receptor in Modulating Cisplatin Sensitivity in Bladder Cancer. Cancers (Basel) 2021; 13:cancers13050975. [PMID: 33652650 PMCID: PMC7956795 DOI: 10.3390/cancers13050975] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 01/06/2021] [Accepted: 02/19/2021] [Indexed: 01/15/2023] Open
Abstract
Simple Summary It remains unclear why chemotherapy is often ineffective in patients with bladder cancer. Meanwhile, we previously reported that male sex hormones (i.e., androgens) could considerably reduce the efficacy of cisplatin, an anti-cancer drug used as the first-line treatment against advanced bladder cancer. The present study aimed to investigate how androgen receptor signaling, which is activated by binding of androgenic hormones, modulates sensitivity to cisplatin treatment in bladder cancer, using cell line models and surgical specimens. We found that the expression levels of the androgen receptor and a molecule (BXDC2) were inversely correlated and that loss of BXDC2 was associated with cisplatin resistance. We thus provide evidence to suggest an underlying molecular mechanism responsible for androgen receptor-induced chemoresistance in bladder cancer. Abstract Underlying mechanisms for resistance to cisplatin-based chemotherapy in bladder cancer patients are largely unknown, although androgen receptor (AR) activity, as well as extracellular signal-regulated kinase (ERK) signaling, has been indicated to correlate with chemosensitivity. We also previously showed ERK activation by androgen treatment in AR-positive bladder cancer cells. Because our DNA microarray analysis in control vs. AR-knockdown bladder cancer lines identified BXDC2 as a potential downstream target of AR, we herein assessed its functional role in cisplatin sensitivity, using bladder cancer lines and surgical specimens. BXDC2 protein expression was considerably downregulated in AR-positive or cisplatin-resistant cells. BXDC2-knockdown sublines were significantly more resistant to cisplatin, compared with respective controls. Without cisplatin treatment, BXDC2-knockdown resulted in significant increases/decreases in cell proliferation/apoptosis, respectively. An ERK activator was also found to reduce BXDC2 expression. Immunohistochemistry showed downregulation of BXDC2 expression in tumor (vs. non-neoplastic urothelium), higher grade/stage tumor (vs. lower grade/stage), and AR-positive tumor (vs. AR-negative). Patients with BXDC2-positive/AR-negative muscle-invasive bladder cancer had a significantly lower risk of disease-specific mortality, compared to those with a BXDC2-negative/AR-positive tumor. Additionally, in those undergoing cisplatin-based chemotherapy, BXDC2 positivity alone (p = 0.083) or together with AR negativity (p = 0.047) was associated with favorable response. We identified BXDC2 as a key molecule in enhancing cisplatin sensitivity. AR-ERK activation may thus be associated with chemoresistance via downregulating BXDC2 expression in bladder cancer.
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25
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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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Nagata Y, Goto T, Jiang G, Teramoto Y, Miyamoto H. 5α-Reductase Inhibitors Do Not Prevent the Development and Progression of Urothelial Cancer: In Vitro Evidence. Bladder Cancer 2020. [DOI: 10.3233/blc-200380] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND: Androgen receptor (AR) activation has been implicated in the pathogenesis of urothelial cancer. However, it remains controversial whether 5α-reductase inhibitors (5α-RIs), which are known for blocking the conversion of testosterone to the more potent androgen dihydrotestosterone and often prescribed for the treatment of, for instance, benign prostatic hyperplasia, contribute to preventing the development of bladder cancer. OBJECTIVE: To determine the role of 5α-RI therapy in urothelial tumorigenesis and tumor progression, using cell line models. METHODS: In a human non-neoplastic urothelial SVHUC subline stably expressing a full-length wild-type human AR (SVHUC-AR) with carcinogen/MCA challenge and human bladder cancer lines, we assessed the effects of three 5α-RIs, dutasteride (up to 100 nM), finasteride (up to 500 nM), and epristeride (up to 5μM), on neoplastic/malignant transformation and cell growth, respectively. RESULTS: In AR-positive bladder cancer UMUC3 and 5637-AR cells, an AR antagonist bicalutamide significantly inhibited their proliferation, whereas three 5α-RIs failed to do. Similarly, these 5α-RIs did not significantly inhibit the migration of bladder cancer cells induced by the treatment of testosterone which could be metabolized into dihydrotestosterone in culture medium. In MCA-SVHUC-AR cells, induction of their neoplastic transformation by testosterone, which was prevented by bicalutamide, was confirmed. However, no significant inhibitory effects of 5α-RIs on the neoplastic transformation of AR-positive urothelial cells treated with or without testosterone were observed. CONCLUSIONS: Using in vitro models for urothelial cancer, 5α-RI treatment even at supra-pharmacological doses was thus found to have no significant impact on the prevention of both tumorigenesis and tumor progression.
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Affiliation(s)
- Yujiro Nagata
- Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
| | - Takuro Goto
- Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
| | - Guiyang Jiang
- Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
| | - Yuki Teramoto
- Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
| | - Hiroshi Miyamoto
- Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
- Department of Urology, University of Rochester Medical Center, Rochester, NY, USA
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Mizushima T, Jiang G, Kawahara T, Li P, Han B, Inoue S, Ide H, Kato I, Jalalizadeh M, Miyagi E, Fukuda M, Reis LO, Miyamoto H. Androgen Receptor Signaling Reduces the Efficacy of Bacillus Calmette-Guérin Therapy for Bladder Cancer via Modulating Rab27b-Induced Exocytosis. Mol Cancer Ther 2020; 19:1930-1942. [PMID: 32737155 DOI: 10.1158/1535-7163.mct-20-0050] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Revised: 06/24/2020] [Accepted: 07/01/2020] [Indexed: 12/24/2022]
Abstract
Although intravesical bacillus Calmette-Guérin (BCG) immunotherapy has been the gold standard for nonsurgical management of non-muscle-invasive bladder cancer, a considerable number of patients exhibit resistance to the adjuvant treatment with unexplained mechanisms. This study aimed to investigate whether and how androgen receptor (AR) signals modulate BCG cytotoxicity in bladder cancer. AR knockdown or overexpression in bladder cancer lines resulted in induction or reduction, respectively, in intracellular BCG quantity and its cytotoxic activity. Microarray screening identified Rab27b, a small GTPase known to mediate bacterial exocytosis, which was upregulated in BCG-resistant cells and downregulated in AR-shRNA cells. Knockdown of Rab27b, or its effector SYTL3, or overexpression of Rab27b also induced or reduced, respectively, BCG quantity and cytotoxicity. In addition, treatment with GW4869, which was previously shown to inhibit Rab27b-dependent secretion, induced them and reduced Rab27b expression in bladder cancer cells. Meanwhile, AR expression was upregulated in BCG-resistant lines, compared with respective controls. In a mouse orthotopic xenograft model, Rab27b/SYTL3 knockdown or GW4869 treatment enhanced the amount of BCG within tumors and its suppressive effect on tumor growth. Moreover, in non-muscle-invasive bladder cancer specimens from patients subsequently undergoing BCG therapy, positivity of AR/Rab27b expression was associated with significantly higher risks of tumor recurrence. AR activation thus correlates with resistance to BCG treatment, presumably via upregulating Rab27b expression. Mechanistically, it is suggested that BCG elimination from urothelial cells is induced by Rab27b/SYTL3-mediated exocytosis. Accordingly, Rab27b inactivation, potentially via antiandrogenic drugs and/or exocytosis inhibition are anticipated to sensitize the efficacy of BCG therapy, especially in patients with BCG-refractory AR/Rab27b-positive bladder cancer.
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Affiliation(s)
- Taichi Mizushima
- Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, New York
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
- James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland
- Department of Obstetrics and Gynecology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Guiyang Jiang
- Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, New York
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York
| | - Takashi Kawahara
- Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, New York
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
- James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland
- Departments of Urology and Renal Transplantation, Yokohama City University Medical Center, Yokohama, Japan
| | - Peng Li
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
- James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Bin Han
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
- James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Satoshi Inoue
- Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, New York
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
- James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Hiroki Ide
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
- James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Ikuma Kato
- Department of Molecular Pathology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Mehrsa Jalalizadeh
- James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Etsuko Miyagi
- Department of Obstetrics and Gynecology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Mitsunori Fukuda
- Department of Integrative Life Sciences, Tohoku University Graduate School of Life Sciences, Sendai, Japan
| | - Leonardo O Reis
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
- James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Hiroshi Miyamoto
- Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, New York.
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
- James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland
- Department of Urology, University of Rochester Medical Center, Rochester, New York
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28
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Fard SS, Saliminejad K, Sotoudeh M, Soleimanifard N, Kouchaki S, Yazdanbod M, Mahmoodzadeh H, Ghavamzadeh A, Malekzadeh R, Chahardouli B, Alimoghaddam K, Ghaffari SH. The Correlation between EGFR and Androgen Receptor Pathways: A Novel Potential Prognostic Marker in Gastric Cancer. Anticancer Agents Med Chem 2020; 19:2097-2107. [PMID: 31566139 DOI: 10.2174/1871520619666190930142820] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Revised: 06/21/2019] [Accepted: 08/07/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND Despite worthy biologic rationale and numerous studies introducing therapeutic strategies targeting Epidermal Growth Factor Receptor (EGFR), phase III clinical trials have claimed that these current anti-EGFR agents did not significantly improve overall survival of Gastric Cancer (GC) patients. Therefore, to discover flawless candidates of anti-EGFR therapy and ideal prognostic markers, innovative studies are warranted. METHODS The aim of this study was to assess the expression profile of EGFR in GC, adjacent non-tumor and normal gastric tissues by qRT-PCR, investigating the association of EGFR expression with clinicopathological features, evaluating possible molecular interaction between EGFR and Androgen Receptor (AR), and elucidating novel prognostic marker using Cox regression model. RESULTS Among 60 GC patients, 70% (42/60) overexpressed EGFR relative to normal gastric tissues. EGFR overexpression was significantly correlated with the AR overexpression in GC patients. Although EGFR overexpression was remarkably associated with unfavorable outcomes (HR= 4.067, 95% CI= 1.228-13.467, p= 0.022), it was not an independent prognostic factor adjusted for other variables. However, we provided evidences that simultaneous evaluation of EGFR and AR expression, could independently predict the outcome of GC patients and could use as a precise prognostic marker. Moreover, it was revealed that induction or inhibition of AR signaling could alter the mRNA expression of EGFR in GC cell lines. CONCLUSION By targeting AR and EGFR using a potent AR inhibitor such as Enzalutamide, we postulate the possible crosstalk between EGFR and AR pathways in GC. Moreover, our study provided evidences elucidating a novel promising marker, simultaneous evaluation of EGFR and AR expression, which could properly predict prognosis of gastric cancer patients.
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Affiliation(s)
- Shahrzad S Fard
- Hematology, Oncology and Stem Cell Transplantation Research Institute, School of Medicine, 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
| | - Masoud Sotoudeh
- Digestive Oncology Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Shaghayegh Kouchaki
- Hematology, Oncology and Stem Cell Transplantation Research Institute, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Habibollah Mahmoodzadeh
- Department of Surgical Oncology, Cancer Institute, Imam Khomeini Hospital Complex, University of Medical Sciences, Tehran, Iran
| | - Ardeshir Ghavamzadeh
- Hematology, Oncology and Stem Cell Transplantation Research Institute, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Reza Malekzadeh
- Digestive Oncology Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Bahram Chahardouli
- 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
| | - Seyed H Ghaffari
- Hematology, Oncology and Stem Cell Transplantation Research Institute, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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Xu C, Sun M, Zhang X, Xu Z, Miyamoto H, Zheng Y. Activation of Glucocorticoid Receptor Inhibits the Stem-Like Properties of Bladder Cancer via Inactivating the β-Catenin Pathway. Front Oncol 2020; 10:1332. [PMID: 32850423 PMCID: PMC7419687 DOI: 10.3389/fonc.2020.01332] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Accepted: 06/25/2020] [Indexed: 12/18/2022] Open
Abstract
Background: Glucocorticoid receptor (GR) signaling pathway has been shown to involve epithelial -to- mesenchymal transition which was implicated in the regulation of bladder cancer stem cells (CSCs) in our previous study. Herein, we aim to figure out how GR affects the stem-like properties of bladder cancer cells. Methods: We used dexamethasone (DEX) treatment or gene-knockdown/-knockout techniques to activate or silence the GR pathway, respectively. Then we applied immunohistochemical staining and flow cytometry to assess the associations between the expression levels of GR and a stem cell surface marker CD44. Stem-like properties were assessed by reactive oxygen species (ROS), sphere-formation and side population assays. The expression levels of cancer stem cell-associated molecules were assessed by quantitative PCR and Western blotting. Tumor growth was compared using mouse xenograft models. Results: In GR-positive bladder cancer cells, DEX significantly reduced the expression of CD44 as well as pluripotency transcription factors including β-catenin and its downstream target (C-MYC, Snail, and OCT-4), the rate of sphere formation, and the proportion of side populations, and induced the intracellular levels of ROS. By contrast, GR silencing in bladder cancer cells showed the opposite effects. In xenograft-bearing mice, GR silencing resulted in the enhancement of tumor growth. Conclusions: These data suggested that GR activity was inversely associated with the stem-like properties of bladder cancer cells, potentially via inactivating the β-catenin pathway.
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Affiliation(s)
- Congcong Xu
- Department of Urology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.,Department of Urology, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Mingwei Sun
- Department of Urology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Xiaozhen Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Zhen Xu
- Department of Urology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Hiroshi Miyamoto
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, United States
| | - Yichun Zheng
- Department of Urology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
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Tripathi A, Gupta S. Androgen receptor in bladder cancer: A promising therapeutic target. Asian J Urol 2020; 7:284-290. [PMID: 32742928 PMCID: PMC7385521 DOI: 10.1016/j.ajur.2020.05.011] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 09/07/2019] [Accepted: 04/16/2020] [Indexed: 12/14/2022] Open
Abstract
There has been a significant progress in the treatment of metastatic urothelial carcinoma in the last few years with the advent of immunotherapy after a long gap of no drug approvals for over 4 decades. While immunotherapy with checkpoint inhibitors has revolutionized the treatment of urothelial carcinoma, unfortunately, only a minority of patients respond to immunotherapy. Treatment options for patients who do not respond and/or progress on immunotherapy are very limited and overall prognosis remains dismal in metastatic urothelial carcinoma. The first targeted therapy targeting the fibroblast growth factor receptor (FGFR) was recently approved for bladder cancer, but it is effective only in select patients harboring the FGFR2 and FGFR 3 mutations. Antibody drug conjugates like enfortumab vedotin have shown promising activity in clinical trials. Development of novel targeted therapies remains an area of investigation and an unmet need in bladder cancer. Exploitation of androgen receptor (AR) is a potential strategy for targeted drug development in bladder cancer. A significant proportion of urothelial carcinoma patients express AR irrespective of gender. AR signaling in urothelial carcinoma has been linked to progression through multiple mechanisms, including activation of human epidermal growth factor receptor-2 (EGFR or HER-2) signaling and epithelial to mesenchymal transition (EMT). Furthermore, AR is enriched in the luminal papillary mRNA subtype of urothelial carcinoma and also mediates resistance to cisplatin-based chemotherapy. Preclinical evidence suggests that AR inhibition can successfully inhibit urothelial carcinoma growth as monotherapy and is synergistic with cisplatin-based chemotherapy. We review the preclinical and clinical evidence supporting the putative role of AR signaling in urothelial carcinoma pathogenesis, progression and its role as a novel therapeutic target and future directions.
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Affiliation(s)
- Abhishek Tripathi
- Section of Hematology Oncology, University of Oklahoma Stephenson Cancer Center, Oklahoma City, OK, USA
| | - Shilpa Gupta
- Department of Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA
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31
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Sanguedolce F, Cormio L, Carrieri G, Calò B, Russo D, Menin A, Pastore AL, Greco F, Bozzini G, Galfano A, Pini G, Porreca A, Mugavero F, Falsaperla M, Ceruti C, Cindolo L, Antonelli A, Minervini A. Role of androgen receptor expression in non-muscle-invasive bladder cancer: a systematic review and meta-analysis. Histol Histopathol 2020; 35:423-432. [PMID: 31803932 DOI: 10.14670/hh-18-189] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
In order to evaluate the potential prognostic/predictive role of androgen receptor (AR) expression in non-muscle-invasive bladder cancer (NMIBC), and whether it may represent a therapeutic target, we conducted a systematic search of the literature using 'androgen receptor or AR', 'testosterone', 'bladder cancer' and 'non-muscle invasive bladder cancer or NMIBC' as keywords. Eleven studies met the inclusion/exclusion criteria. No significant association was found between AR status and patients' gender (p=0.232), tumor size (p=0.975), tumor stage (p=0.237), tumor grade (p=0.444), tumor multicentricity (p=0.397), concomitant CIS (p=0.316) and progression of disease (p=0.397). On the other hand, relative lack of AR expression was significantly correlated to recurrent disease (p=0.001). Evidence for a direct correlation between AR expression and recurrence-free survival of patients with NMIBC indicate ARs as potential markers of BC behavior; moreover, the finding of a role of androgen blockade therapy in improving survival highlights the potential clinical application of this pathway, which deserves to be further explored.
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Affiliation(s)
- Francesca Sanguedolce
- Department of Pathology, University Hospital, Foggia, Italy.
- AGILE Group (Italian Group for Advanced Laparoscopic and Robotic Urologic Surgery), Italy
| | - Luigi Cormio
- Department of Urology and Organ Transplantation, University of Foggia, Foggia, Italy
| | - Giuseppe Carrieri
- Department of Urology and Organ Transplantation, University of Foggia, Foggia, Italy
| | - Beppe Calò
- Department of Urology and Organ Transplantation, University of Foggia, Foggia, Italy
| | - Davide Russo
- Department of Pathology, University Hospital, Foggia, Italy
| | - Andrea Menin
- Department of Pathology, San Bortolo Hospital, Vicenza, Italy
| | - Antonio Luigi Pastore
- AGILE Group (Italian Group for Advanced Laparoscopic and Robotic Urologic Surgery), Italy
- Department of Medico-Surgical Sciences and Biotechnologies, Urology Unit, Sapienza University of Rome, Latina, Italy
| | - Francesco Greco
- AGILE Group (Italian Group for Advanced Laparoscopic and Robotic Urologic Surgery), Italy
- Department of Urology, Humanitas Gavazzeni, Bergamo, Italy
| | - Giorgio Bozzini
- AGILE Group (Italian Group for Advanced Laparoscopic and Robotic Urologic Surgery), Italy
- Department of Urology, ASST Valle Olona, Busto A. (VA), Italy
| | - Antonio Galfano
- AGILE Group (Italian Group for Advanced Laparoscopic and Robotic Urologic Surgery), Italy
- Department of Urology, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Giovannalberto Pini
- AGILE Group (Italian Group for Advanced Laparoscopic and Robotic Urologic Surgery), Italy
- Department of Urology, San Raffaele Turro Hospital, San Raffaele University, Milan, Italy
| | - Angelo Porreca
- AGILE Group (Italian Group for Advanced Laparoscopic and Robotic Urologic Surgery), Italy
- Urology Unit, Policlinico of Abano, Abano Terme, Italy
| | - Filippo Mugavero
- AGILE Group (Italian Group for Advanced Laparoscopic and Robotic Urologic Surgery), Italy
- Urology Unit, Ospedale Vittorio Emanuele, Catania, Italy
| | - Mario Falsaperla
- AGILE Group (Italian Group for Advanced Laparoscopic and Robotic Urologic Surgery), Italy
- Urology Unit, Ospedale Vittorio Emanuele, Catania, Italy
| | - Carlo Ceruti
- AGILE Group (Italian Group for Advanced Laparoscopic and Robotic Urologic Surgery), Italy
- Urology Clinic, Città della Salute e della Scienza, University of Turin, Turin, Italy
| | - Luca Cindolo
- AGILE Group (Italian Group for Advanced Laparoscopic and Robotic Urologic Surgery), Italy
- Department of Urology, ASL02 Abruzzo, Chieti, Italy
| | - Alessandro Antonelli
- AGILE Group (Italian Group for Advanced Laparoscopic and Robotic Urologic Surgery), Italy
- Urology Unit, ASST-Spedali Civili, Brescia, Italy
| | - Andrea Minervini
- AGILE Group (Italian Group for Advanced Laparoscopic and Robotic Urologic Surgery), Italy
- Department of Oncologic, Minimally-Invasive Urology and Andrology, Careggi Hospital, University of Florence, Florence, Italy
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Integrin αvβ3 in the Mediating Effects of Dihydrotestosterone and Resveratrol on Breast Cancer Cell Proliferation. Int J Mol Sci 2020; 21:ijms21082906. [PMID: 32326308 PMCID: PMC7216104 DOI: 10.3390/ijms21082906] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 04/16/2020] [Accepted: 04/17/2020] [Indexed: 12/16/2022] Open
Abstract
Hormones and their receptors play an important role in the development and progression of breast cancer. Hormones regulate the proliferation of breast cancer cells through binding between estrogen or progestins and steroid receptors that may reside in the cytoplasm or be transcriptionally activated as steroid–protein nuclear receptor complexes. However, receptors for nonpeptide hormones also exist in the plasma membrane. Via those receptors, hormones are able to stimulate breast cancer cell proliferation when activated. Integrins are heterodimeric structural proteins of the plasma membrane. Their primary functions are to interact with extracellular matrix proteins and growth factors. Recently, integrin αvβ3 has been identified as a receptor for nonpeptide hormones, such as thyroid hormone and dihydrotestosterone (DHT). DHT promotes the proliferation of human breast cancer cells through binding to integrin αvβ3. A receptor for resveratrol, a polyphenol stilbene, also exists on this integrin in breast cancer cells, mediating the anti-proliferative, pro-apoptotic action of the compound in these cells. Unrelated activities of DHT and resveratrol that originate at integrin depend upon downstream stimulation of mitogen-activated protein kinase (MAPK, ERK1/2) activity, suggesting the existence of distinct, function-specific pools of ERK1/2 within the cell. This review will discuss the features of these receptors in breast cancer cells, in turn suggesting clinical applications that are based on the interactions of resveratrol/DHT with integrin αvβ3 and other androgen receptors.
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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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Quan Y, Lei H, Wahafu W, Liu Y, Ping H, Zhang X. Inhibition of autophagy enhances the anticancer effect of enzalutamide on bladder cancer. Biomed Pharmacother 2019; 120:109490. [DOI: 10.1016/j.biopha.2019.109490] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Revised: 09/14/2019] [Accepted: 09/22/2019] [Indexed: 10/25/2022] Open
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Melegh Z, Oltean S. Targeting Angiogenesis in Prostate Cancer. Int J Mol Sci 2019; 20:E2676. [PMID: 31151317 PMCID: PMC6600172 DOI: 10.3390/ijms20112676] [Citation(s) in RCA: 101] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Revised: 05/24/2019] [Accepted: 05/29/2019] [Indexed: 02/07/2023] Open
Abstract
Prostate cancer is the most commonly diagnosed cancer among men in the Western world. Although localized disease can be effectively treated with established surgical and radiopharmaceutical treatments options, the prognosis of castration-resistant advanced prostate cancer is still disappointing. The objective of this study was to review the role of angiogenesis in prostate cancer and to investigate the effectiveness of anti-angiogenic therapies. A literature search of clinical trials testing the efficacy of anti-angiogenic therapy in prostate cancer was performed using Pubmed. Surrogate markers of angiogenic activity (microvessel density and vascular endothelial growth factor A (VEGF-A) expression) were found to be associated with tumor grade, metastasis, and prognosis. Six randomizedstudies were included in this review: two phase II trials on localized and hormone-sensitive disease (n = 60 and 99 patients) and four phase III trials on castration-resistant refractory disease (n = 873 to 1224 patients). Although the phase II trials showed improved relapse-free survival and stabilisation of the disease, the phase III trials found increased toxicity and no significant improvement in overall survival. Although angiogenesis appears to have an important role in prostate cancer, the results of anti-angiogenic therapy in castration-resistant refractory disease have hitherto been disappointing. There are various possible explanations for this lack of efficacy in castration-resistant refractory disease: redundancy of angiogenic pathways, molecular heterogeneity of the disease, loss of tumor suppressor protein phosphatase and tensin homolog (PTEN) expression as well as various VEGF-A splicing isoforms with pro- and anti-angiogenic activity. A better understanding of the molecular mechanisms of angiogenesis may help to develop effective anti-angiogenic therapy in prostate cancer.
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Affiliation(s)
- Zsombor Melegh
- Department of Cellular Pathology, Southmead Hospital, Bristol BS10 5NB, UK.
| | - Sebastian Oltean
- Institute of Biomedical and Clinical Sciences, Medical School, College of Medicine and Health, University of Exeter, Exeter EX12LU, UK.
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36
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Tyagi A, Chandrasekaran B, Kolluru V, Rai S, Jordan AC, Houda A, Messer J, Ankem M, Damodaran C, Haddad A. Combination of androgen receptor inhibitor and cisplatin, an effective treatment strategy for urothelial carcinoma of the bladder. Urol Oncol 2019; 37:492-502. [PMID: 31006613 DOI: 10.1016/j.urolonc.2019.03.008] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Revised: 02/05/2019] [Accepted: 03/10/2019] [Indexed: 12/28/2022]
Abstract
PURPOSE The role of androgen receptor (AR) signaling in bladder cancer (BCa) is not fully characterized. This study aimed to delineate the role of AR signaling in BCa and to determine whether the combination of AR inhibitor, Enzalutamide (Enz), and Cisplatin (Cis) efficiently inhibit the growth of BCa cells. METHODS AR expression was determined in 89 human urothelial BCa specimens by immunohistochemistry. A panel of BCa cell lines was treated with Cis, Enz, or a combination of both (Enz + Cis). We determined the expression of AR, changes in apoptotic signaling, DNA damage, and analyzed effect on epithelial mesenchymal transformation markers. RESULT AR expression was detected in 61.4% of tumors from male BCa patients. Inhibition of AR signaling by Enz effectively inhibited the growth of AR+ BCa cells by inducing apoptosis (26%) in AR+ TCCSUP (P = 0.0201) and J82 (15%, P = 0.0386) cells. Interestingly, Enz + Cis synergistically inhibited the proliferation of BCa cells even at low concentrations by inducing proapoptotic signaling in AR+ BCa cells. Invasive and migratory potential of TCCSUP and J82 cells were reduced with Enz + Cis treatment, and associated with down-regulation of mesenchymal markers. CONCLUSIONS A high percentage of the bladder tumors from male patients in our cohort expressed AR. The combination of Enz and Cis synergistically inhibited growth of BCa cells more efficiently than single agent alone. This supports the rationale for future investigation of AR antagonists in combination with standard chemotherapy in MIBC.
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Affiliation(s)
- Ashish Tyagi
- Department of Urology, University of Louisville, Louisville, KY
| | | | | | - Samarpit Rai
- Department of Urology, University of Louisville, Louisville, KY
| | | | - Alatassi Houda
- Department of Pathology, University of Louisville, Louisville, KY
| | - Jamie Messer
- Department of Urology, University of Louisville, Louisville, KY
| | - Murali Ankem
- Department of Urology, University of Louisville, Louisville, KY
| | | | - Ahmed Haddad
- Department of Urology, University of Louisville, Louisville, KY.
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Sikic D, Wirtz RM, Wach S, Dyrskjøt L, Erben P, Bolenz C, Breyer J, Otto W, Hoadley KA, Lerner SP, Eckstein M, Hartmann A, Keck B. Androgen Receptor mRNA Expression in Urothelial Carcinoma of the Bladder: A Retrospective Analysis of Two Independent Cohorts. Transl Oncol 2019; 12:661-668. [PMID: 30831560 PMCID: PMC6403442 DOI: 10.1016/j.tranon.2019.01.005] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Revised: 01/11/2019] [Accepted: 01/21/2019] [Indexed: 01/19/2023] Open
Abstract
INTRODUCTION: Gender-specific differences have led to the androgen receptor (AR) being considered a possible factor in the pathophysiology of urothelial carcinoma of the bladder (UCB), but the exact role remains unclear. MATERIALS AND METHODS: The association of AR mRNA expression with clinicopathological features was retrospectively analyzed in two previously described cohorts. The first cohort consisted of 41 patients with all stages of UCB treated at Aarhus University Hospital, Denmark. The second cohort consisted of 323 patients with muscle-invasive bladder cancer (MIBC) accumulated by the Cancer Genome Atlas (TCGA) Research Network. RESULTS: AR mRNA expression is significantly higher in non-muscle-invasive bladder cancer (NMIBC) when compared to MIBC (P = .0004), with no relevant changes within the different stages of MIBC. AR mRNA expression was significantly associated with TCGA molecular subtypes (P < .0001). In the total cohort, there was no association between AR expression and gender (P = .23). When analyzed separately, females showed a significantly worse disease-free (P = .03) and overall survival (P = .02) when expressing AR mRNA above median level, while the same was not observed for men. Multivariable Cox's regression analyses revealed AR mRNA expression to be an independent prognostic marker for disease-free survival in women (P = .007). CONCLUSIONS: AR mRNA expression is significantly higher in NMIBC than in MIBC, while high AR mRNA expression is associated with worse survival in females with MIBC. Further studies need to investigate the gender-specific role of AR in UCB.
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Affiliation(s)
- Danijel Sikic
- Department of Urology and Pediatric Urology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
| | - Ralph M Wirtz
- STRATIFYER Molecular Pathology GmbH, Cologne, Germany.
| | - Sven Wach
- Department of Urology and Pediatric Urology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
| | - Lars Dyrskjøt
- Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
| | - Philipp Erben
- Department of Urology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
| | - Christian Bolenz
- Department of Urology and Pediatric Urology, University Hospital Ulm, Ulm, Germany.
| | - Johannes Breyer
- Department of Urology, University of Regensburg, Regensburg, Germany.
| | - Wolfgang Otto
- Department of Urology, University of Regensburg, Regensburg, Germany.
| | - Katherine A Hoadley
- Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
| | - Seth P Lerner
- Department of Urology, Baylor College of Medicine, Houston, TX, USA.
| | - Markus Eckstein
- Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
| | - Arndt Hartmann
- Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
| | - Bastian Keck
- Department of Urology and Pediatric Urology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
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Tao T, Su Q, Xu S, Deng J, Zhou S, Zhuang Y, Huang Y, He C, He S, Peng M, Hocher B, Yang X. Down-regulation of PKM2 decreases FASN expression in bladder cancer cells through AKT/mTOR/SREBP-1c axis. J Cell Physiol 2019; 234:3088-3104. [PMID: 30221356 DOI: 10.1002/jcp.27129] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2018] [Accepted: 07/06/2018] [Indexed: 12/30/2022]
Abstract
Fatty acid synthase (FASN) catalyzing the terminal steps in the de novo biogenesis of fatty acids is correlated with low survival and high disease recurrence in patients with bladder cancer. Pyruvate kinase M2 (PKM2) regulates the final step of glycolysis levels and provides a growth advantage to tumors. However, it is unclear whether the change of PKM2 has an effect on FASN and what is the mechanisms underlying. Here we describe a novel function of PKM2 in control of lipid metabolism by mediating transcriptional activation of FASN, showing the reduced expression of sterol regulatory element binding protein 1c (SREBP-1c). We first discovered that PKM2 physically interacts with the SREBP-1c using biochemical approaches, and downregulation of PKM2 reduced the expression of SREBP-1c by inactivating the AKT/mTOR signaling pathway, which in turn directly suppressed the transcription of major lipogenic genes FASN to reduce tumor growths. Furthermore, either PKM2 inhibitor-Shikonin or FASN inhibitor-TVB-3166 alone induced a strong antiproliferative and anticolony forming effect in bladder cancer cell line. The combination of both inhibitors exhibits a super synergistic effect on blocking the bladder cancer cells growth. It provides a new target and scientific basis for the treatment of bladder cancer.
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Affiliation(s)
- Ting Tao
- Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan, China
| | - Qiongli Su
- Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan, China
- Department of Pharmacy, Central Hospital of Zhuzhou City and Affiliated Zhuzhou Hospital of Xiangya Medical College of Central South University, Hunan, China
| | - Simeng Xu
- Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan, China
| | - Jun Deng
- Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan, China
| | - Sichun Zhou
- Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan, China
| | - Yu Zhuang
- Animal Nutrition and Human Health Laboratory, Hunan Normal University, Changsha, Hunan, China
| | - Yanjun Huang
- Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan, China
| | - Caimei He
- Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan, China
| | - Shanping He
- Animal Nutrition and Human Health Laboratory, Hunan Normal University, Changsha, Hunan, China
| | - Mei Peng
- Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan, China
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Berthold Hocher
- Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan, China
- Institute for Nutritional Science, University of Potsdam, Potsdam, Germany
| | - Xiaoping Yang
- Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan, China
- Animal Nutrition and Human Health Laboratory, Hunan Normal University, Changsha, Hunan, China
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Wen L, Zhang X, Bian J, Han L, Huang H, He M, Wei M, Wang P. The long non-coding RNA LINC00460 predicts the prognosis and promotes the proliferation and migration of cells in bladder urothelial carcinoma. Oncol Lett 2019; 17:3874-3880. [PMID: 30881506 PMCID: PMC6403511 DOI: 10.3892/ol.2019.10023] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Accepted: 01/24/2019] [Indexed: 12/20/2022] Open
Abstract
Long non-coding RNAs (lncRNAs) may serve an important role in cancer development and may also be suitable for use as prognostic biomarkers. At present, the role of lncRNAs in bladder cancer remains unclear. The present study examined the potential involvement of lncRNA LINC00460 in bladder urothelial carcinoma using data from The Caner Genome Atlas (TCGA) and cell line experiments. The results indicated that LINC00460 expression levels were increased in bladder urothelial carcinoma tissues and bladder cancer 5637 and T24 cell lines compared with corresponding normal controls (P<0.05). TCGA data indicated that LINC00460 expression was negatively correlated with a positive prognosis in patients with bladder urothelial carcinoma (P<0.05). Consistently, the downregulation of LINC00460 with short hairpin RNA significantly suppressed 5637 and T24 cell proliferation and migration. Therefore, it was suggested that strategies that target LINC00460 may be developed as novel therapeutic approaches for the treatment of bladder cancer. In addition, the expression level of androgen receptor (AR) was downregulated in bladder urothelial carcinoma tissues and exhibited a negative correlation with the expression level of LINC00460 (r=−0.43; P<0.0001), based on the data from TCGA. We hypothesized that LINC00460 may serve an oncogenic role by regulating the expression of AR.
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Affiliation(s)
- Lijie Wen
- Department of Urology, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning 110032, P.R. China
| | - Xiling Zhang
- Department of Urology, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning 110032, P.R. China
| | - Jing Bian
- School of Pharmacy, Department of Pharmacology, China Medical University, Shenyang, Liaoning 110122, P.R. China
| | - Li Han
- School of Pharmacy, Department of Pharmacology, China Medical University, Shenyang, Liaoning 110122, P.R. China
| | - Haibo Huang
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Miao He
- School of Pharmacy, Department of Pharmacology, China Medical University, Shenyang, Liaoning 110122, P.R. China
| | - Minjie Wei
- School of Pharmacy, Department of Pharmacology, China Medical University, Shenyang, Liaoning 110122, P.R. China
| | - Ping Wang
- Department of Urology, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning 110032, P.R. China
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Liang Z, Chen Y, Wang L, Li D, Yang X, Ma G, Wang Y, Li Y, Zhao H, Liang Y, Niu H. CYP27A1 inhibits bladder cancer cells proliferation by regulating cholesterol homeostasis. Cell Cycle 2018; 18:34-45. [PMID: 30563407 DOI: 10.1080/15384101.2018.1558868] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022] Open
Abstract
CYP27A1, an enzyme involved in regulating cellular cholesterol homeostasis, converts cholesterol into 27-hydroxycholesterol (27-HC). The relationship between CYP27A1 and cell proliferation was studied to determine the role of CYP27A1 in bladder cancer. The expression of CYP27A1 in three bladder cancer cell lines (T24, UM-UC-3 and 5637) were assessed by qRT-PCR and Western blotting, and cells with stable CYP27A1 expression were generated by lentiviral infection. Cell proliferation was detected by MTT assays, colony formation assays and a tumor xenograft model in vitro and in vivo, and the intracellular 27-HC and cholesterol secretion levels were detected by enzyme-linked immunosorbent assays (ELISA). The results revealed that CYP27A1 expression was downregulated in androgen receptor (AR)-positive T24/UM-UC-3 cells compared with AR-negative 5637 cell. After CYP27A1 expression was restored, cell proliferation was inhibited in vitro and in vivo because much more intracellular 27-HC was produced in the CYP27A1-overexpressing cells than in the control cells. Both T24 and UM-UC-3 cells treated with 27-HC showed similar results. In addition, CYP27A1/27HC could reduce the cellular cholesterol level in both T24 and UM-UC-3 cells by upregulating ATP-binding cassette transporters G1 and A1 (ABCG1 and ABCA1) through Liver X receptors (LXRs) pathway and downregulating low-density lipoprotein receptor (LDLR) expression. These findings all suggest that CYP27A1 is a critical cholesterol sensor in bladder cancer cells that may contribute significantly to bladder cancer proliferation.
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Affiliation(s)
- Zhijuan Liang
- a Key Laboratory, Department of Urology and Andrology , Affiliated Hospital of Qingdao University , Qingdao , China
| | - Yuanbin Chen
- a Key Laboratory, Department of Urology and Andrology , Affiliated Hospital of Qingdao University , Qingdao , China
| | - Liping Wang
- a Key Laboratory, Department of Urology and Andrology , Affiliated Hospital of Qingdao University , Qingdao , China
| | - Dan Li
- a Key Laboratory, Department of Urology and Andrology , Affiliated Hospital of Qingdao University , Qingdao , China
| | - Xuecheng Yang
- b Department of Urology , Affiliated Hospital of Qingdao University , Qingdao , China
| | - Guofeng Ma
- b Department of Urology , Affiliated Hospital of Qingdao University , Qingdao , China
| | - Yonghua Wang
- b Department of Urology , Affiliated Hospital of Qingdao University , Qingdao , China
| | - Yongxin Li
- c Department of Vascular Surgery , Affiliated Hospital of Qingdao University , Qingdao , China
| | - Han Zhao
- d Department of Pathology , Affiliated Hospital of Qingdao University , Qingdao , China
| | - Ye Liang
- a Key Laboratory, Department of Urology and Andrology , Affiliated Hospital of Qingdao University , Qingdao , China
| | - Haitao Niu
- a Key Laboratory, Department of Urology and Andrology , Affiliated Hospital of Qingdao University , Qingdao , China.,b Department of Urology , Affiliated Hospital of Qingdao University , Qingdao , China
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Inoue S, Mizushima T, Ide H, Jiang G, Goto T, Nagata Y, Netto GJ, Miyamoto H. ATF2 promotes urothelial cancer outgrowth via cooperation with androgen receptor signaling. Endocr Connect 2018; 7:1397-1408. [PMID: 30521479 PMCID: PMC6280600 DOI: 10.1530/ec-18-0364] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Accepted: 11/09/2018] [Indexed: 11/09/2022]
Abstract
We investigated the functional role of ATF2, a transcription factor normally activated via its phosphorylation in response to phospho-ERK/MAPK signals, in the outgrowth of urothelial cancer. In both neoplastic and non-neoplastic urothelial cells, the expression levels of androgen receptor (AR) correlated with those of phospho-ATF2. Dihydrotestosterone treatment in AR-positive bladder cancer cells also induced the expression of phospho-ATF2 and phospho-ERK as well as nuclear translocation and transcriptional activity of ATF2. Meanwhile, ATF2 knockdown via shRNA resulted in significant decreases in cell viability, migration and invasion of AR-positive bladder cancer lines, but not AR-negative lines, as well as significant increases and decreases in apoptosis or G0/G1 cell cycle phase and S or G2/M phase, respectively. Additionally, the growth of AR-positive tumors expressing ATF2-shRNA in xenograft-bearing mice was retarded, compared with that of control tumors. ATF2 knockdown also resulted in significant inhibition of neoplastic transformation induced by a chemical carcinogen 3-methylcholanthrene, as well as the expression of Bcl-2/cyclin-A2/cyclin-D1/JUN/MMP-2, in immortalized human normal urothelial SVHUC cells stably expressing AR, but not AR-negative SVHUC cells. Finally, immunohistochemistry in surgical specimens demonstrated significant elevation of ATF2/phospho-ATF2/phospho-ERK expression in bladder tumors, compared with non-neoplastic urothelial tissues. Multivariate analysis further showed that moderate/strong ATF2 expression and phospho-ATF2 positivity were independent predictors for recurrence of low-grade tumors (hazard ratio (HR) = 2.956, P = 0.045) and cancer-specific mortality of muscle-invasive tumors (HR = 5.317, P = 0.012), respectively. Thus, ATF2 appears to be activated in urothelial cells through the AR pathway and promotes the development and progression of urothelial cancer.
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Affiliation(s)
- Satoshi Inoue
- Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, New York, USA
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Taichi Mizushima
- Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, New York, USA
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Hiroki Ide
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Guiyang Jiang
- Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, New York, USA
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA
| | - Takuro Goto
- Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, New York, USA
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA
| | - Yujiro Nagata
- Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, New York, USA
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA
| | - George J Netto
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Hiroshi Miyamoto
- Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, New York, USA
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Urology, University of Rochester Medical Center, Rochester, New York, USA
- Correspondence should be addressed to H Miyamoto:
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Erben P, Sikic D, Wirtz RM, Martini T, Weis CA, Breyer J, Otto W, Keck B, Hartmann A, Bolenz C. Analysis of the prognostic relevance of sex-steroid hormonal receptor mRNA expression in muscle-invasive urothelial carcinoma of the urinary bladder. Virchows Arch 2018; 474:209-217. [PMID: 30483954 DOI: 10.1007/s00428-018-2496-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Revised: 10/10/2018] [Accepted: 11/19/2018] [Indexed: 12/20/2022]
Abstract
Muscle-invasive urothelial carcinoma of the urinary bladder (UCB) often recurs following radical cystectomy (RC). An altered expression of sex-steroid hormone receptors has been associated with oncological outcomes of UCB and may represent therapeutic targets. Here the expression of different hormone receptors was measured on mRNA levels in patients treated by RC and associated with outcomes. Androgen receptor (AR), estrogen receptor 1 (ESR1), and progesterone receptor (PGR) mRNA expression was assessed by quantitative reverse transcription polymerase chain reaction (RT-qPCR) in RC samples of 87 patients with a median age of 66 (39-88) years. Univariate and multivariate analyses were performed to test associations with pathological and clinical characteristics as well as recurrence-free (RFS) and disease-specific survival (DSS). AR mRNA expression was lower in comparison with ESR1 and PGR expression (p < 0.0001). In univariate analysis, high expression levels of AR were associated with reduced RFS (HR 2.8, p = 0.015) and DSS (HR 2.8, p = 0.010). High AR mRNA expression and a positive lymph node status were independent predictors for reduced RFS (HR 2.5, p = 0.0049) and DSS (HR 3.4, p = 0.009). In patients with low AR mRNA expression, an increased ESR1 and PGR mRNA expression were associated with reduced RFS and DSS. High expression levels of AR are significantly associated with adverse outcome in patients with muscle-invasive UCB following RC. ESR1 and PGR expression status can further stratify patients with low AR expression into subgroups with significantly reduced RFS and DSS. Therapeutic targeting of AR may influence outcomes in patients with UCB.
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Affiliation(s)
- Philipp Erben
- Department of Urology, University Medical Centre Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Danijel Sikic
- Department of Urology and Pediatric Urology, Friedrich-Alexander University (FAU) Erlangen-Nürnberg, Erlangen, Germany.
| | - Ralph M Wirtz
- Stratifyer Molecular Pathology GmbH, Cologne, Germany
| | - Thomas Martini
- Department of Urology and Pediatric Urology, University of Ulm, Ulm, Germany
| | - Cleo-Aron Weis
- Institute of Pathology, University Medical Centre Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Johannes Breyer
- Department of Urology, University of Regensburg, Regensburg, Germany
| | - Wolfgang Otto
- Department of Urology, University of Regensburg, Regensburg, Germany
| | - Bastian Keck
- Department of Urology and Pediatric Urology, Friedrich-Alexander University (FAU) Erlangen-Nürnberg, Erlangen, Germany
| | - Arndt Hartmann
- Institute of Pathology, Friedrich-Alexander University (FAU) Erlangen-Nürnberg, Erlangen, Germany
| | - Christian Bolenz
- Department of Urology and Pediatric Urology, University of Ulm, Ulm, Germany
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Liu Y, Ding M, Liao X, Gao Q, He A, Liu B, Hu K, Xie H, Zhou Q, Zhan H, Liu Y, Huang W, Mei H. High expression of enhancer RNA MARC1 or its activation by DHT is associated with the malignant behavior in bladder cancer. Exp Cell Res 2018; 370:303-311. [PMID: 29964053 DOI: 10.1016/j.yexcr.2018.06.032] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2018] [Revised: 06/18/2018] [Accepted: 06/27/2018] [Indexed: 12/14/2022]
Abstract
Enhancer RNAs (eRNAs), a subclass of noncoding RNA from enhancers, have biological functions in gene expression. However, their potential role in bladder cancer (BCa) remains largely unknown. The present study investigated the functional role of androgen-associated androgen receptor (AR) mediated-eRNA MARC1 (eMARC1) in BCa progression. Cell proliferation, migration, and apoptosis of BCa cell lines (5637 and T24) with different eMARC1 expression levels or treated with 5α-dehydrotestosterone (DHT) were investigated. In the current study, we discovered that eMARC1 was highly expressed in BCa tissues and cell lines, and eMARC1 overexpression promoted the progression of BCa cells, while knockdown of eMARC1 suppressed tumorigenesis. DHT treatment significantly elevated eMARC1 expression levels, which also facilitated cell proliferation, motility, and inhibited cell apoptosis. We further found that eMARC1 silencing impaired the androgenic effect of DHT in BCa cells. These results suggested that eMARC1 exerted its effects on BCa cell progression, and DHT promoted bladder cancer progression by activating eMARC1.
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Affiliation(s)
- Yuhan Liu
- Department of Urology, Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen 518000, China
| | - Mengting Ding
- Department of Urology, Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen 518000, China; Department of Urology, Shenzhen Second People's Hospital, Clinical Medicine College of Anhui Medical University, Shenzhen 518000, Guangdong, China
| | - Xinhui Liao
- Department of Urology, Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen 518000, China
| | - Qunjun Gao
- Department of Urology, Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen 518000, China; Departmentof Urology, Shenzhen Second People's Hospital, Graduate School of Guangzhou Medical University, Guangzhou Medical University, Guangzhou 511436, China
| | - Anbang He
- Department of Urology, Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen 518000, China
| | - Baoer Liu
- Department of Urology, Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen 518000, China
| | - Kun Hu
- Department of Urology, Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen 518000, China; Department of Urology, Shenzhen Second People's Hospital, Clinical Medicine College of Anhui Medical University, Shenzhen 518000, Guangdong, China
| | - Haibiao Xie
- Department of Urology, Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen 518000, China
| | - Qun Zhou
- Department of Urology, Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen 518000, China; Department of Urology, Shenzhen Second People's Hospital, Clinical Medicine College of Anhui Medical University, Shenzhen 518000, Guangdong, China
| | - Hengji Zhan
- Department of Urology, Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen 518000, China
| | - Yuchen Liu
- Department of Urology, Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen 518000, China.
| | - Weiren Huang
- Department of Urology, Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen 518000, China.
| | - Hongbing Mei
- Department of Urology, Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen 518000, China.
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Ide H, Inoue S, Mizushima T, Jiang G, Chuang KH, Oya M, Miyamoto H. Androgen Receptor Signaling Reduces Radiosensitivity in Bladder Cancer. Mol Cancer Ther 2018; 17:1566-1574. [PMID: 29720561 DOI: 10.1158/1535-7163.mct-17-1061] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Revised: 12/28/2017] [Accepted: 04/27/2018] [Indexed: 11/16/2022]
Abstract
Although radiotherapy often with chemotherapy has been shown to offer a survival benefit comparable with that of radical cystectomy in select patients with bladder cancer, the development of radiosensitization strategies may significantly enhance its application. Notably, emerging preclinical evidence has indicated the involvement of androgen receptor (AR) signaling in urothelial cancer progression. We here assessed whether AR signals could contribute to modulating radiosensitivity in bladder cancer cells. Ionizing radiation reduced the numbers of viable cells or colonies of AR-negative lines more significantly than those of AR-positive lines. Similarly, in AR-positive cells cultured in androgen-depleted conditions, dihydrotestosterone treatment lowered the effects of irradiation. Meanwhile, an antiandrogen hydroxyflutamide enhanced them in AR-positive cells cultured in the presence of androgens. AR knockdown or hydroxyflutamide treatment also resulted in a delay in DNA double-strand break repair 4-24 hours after irradiation. We then established "radiation-resistant" sublines and found considerable elevation of the expression of AR as well as DNA repair genes, such as ATR, CHEK1, and PARP-1, in these sublines, compared with respective controls. Furthermore, dihydrotestosterone induced the expression of these DNA repair genes in irradiated AR-positive cells, and hydroxyflutamide antagonized the androgen effects. Finally, in a mouse xenograft model, low-dose flutamide was found to enhance the inhibitory effects of irradiation, and its tumor size was similar to that of AR knockdown line with radiation alone. These findings suggest that AR activity inversely correlates with radiosensitivity in bladder cancer. Accordingly, antiandrogenic drugs may function as sensitizers of irradiation, especially in patients with AR-positive urothelial cancer. Mol Cancer Ther; 17(7); 1566-74. ©2018 AACR.
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Affiliation(s)
- Hiroki Ide
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.,James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Urology, Keio University School of Medicine, Tokyo, Japan
| | - Satoshi Inoue
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.,James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, New York.,James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York
| | - Taichi Mizushima
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.,James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, New York.,James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York
| | - Guiyang Jiang
- Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, New York.,James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York
| | - Kuang-Hsiang Chuang
- Department of Radiation Oncology, University of Rochester Medical Center, Rochester, New York
| | - Mototsugu Oya
- Department of Urology, Keio University School of Medicine, Tokyo, Japan
| | - Hiroshi Miyamoto
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland. .,James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, New York.,James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York.,Department of Urology, University of Rochester Medical Center, Rochester, New York
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Inoue S, Mizushima T, Miyamoto H. Role of the androgen receptor in urothelial cancer. Mol Cell Endocrinol 2018; 465:73-81. [PMID: 28652170 DOI: 10.1016/j.mce.2017.06.021] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Revised: 06/19/2017] [Accepted: 06/21/2017] [Indexed: 12/22/2022]
Abstract
Men have had a substantially higher risk of developing bladder cancer than women. This has prompted research on androgen-mediated androgen receptor (AR) signaling in urothelial cancer. Indeed, increasing preclinical evidence indicates that AR activation correlates with the promotion of urothelial carcinogenesis and tumor outgrowth. In this article, we summarize and discuss available data suggesting the involvement of androgens and the AR pathway in the development and progression of urothelial cancer. Although precise mechanisms for the functions of AR and related signals in urothelial cells remain far from being fully understood, current observations may offer effective chemopreventive and therapeutic approaches for urothelial cancer. Clinical application of various anti-AR therapies available for AR-dependent prostate cancer to urothelial cancer patients is thus anticipated.
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Affiliation(s)
- Satoshi Inoue
- Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA; James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
| | - Taichi Mizushima
- Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA; James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
| | - Hiroshi Miyamoto
- Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA; James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA; Department of Urology, University of Rochester Medical Center, Rochester, NY, USA.
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Inoue S, Ide H, Mizushima T, Jiang G, Netto GJ, Gotoh M, Miyamoto H. Nuclear Factor-κB Promotes Urothelial Tumorigenesis and Cancer Progression via Cooperation with Androgen Receptor Signaling. Mol Cancer Ther 2018; 17:1303-1314. [PMID: 29592878 DOI: 10.1158/1535-7163.mct-17-0786] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2017] [Revised: 12/13/2017] [Accepted: 03/14/2018] [Indexed: 11/16/2022]
Abstract
We investigated the role of NF-κB in the development and progression of urothelial cancer as well as cross-talk between NF-κB and androgen receptor (AR) signals in urothelial cells. Immunohistochemistry in surgical specimens showed that the expression levels of NF-κB/p65 (P = 0.015)/phospho-NF-κB/p65 (P < 0.001) were significantly elevated in bladder tumors, compared with those in nonneoplastic urothelial tissues. The rates of phospho-NF-κB/p65 positivity were also significantly higher in high-grade (P = 0.015)/muscle-invasive (P = 0.033) tumors than in lower grade/non-muscle-invasive tumors. Additionally, patients with phospho-NF-κB/p65-positive muscle-invasive bladder cancer had significantly higher risks of disease progression (P < 0.001) and cancer-specific mortality (P = 0.002). In immortalized human normal urothelial SVHUC cells stably expressing AR, NF-κB activators and inhibitors accelerated and prevented, respectively, their neoplastic transformation induced by a chemical carcinogen 3-methylcholanthrene. Bladder tumors were identified in 56% (mock), 89% (betulinic acid), and 22% (parthenolide) of N-butyl-N-(4-hydroxybutyl)nitrosamine-treated male C57BL/6 mice at 22 weeks of age. NF-κB activators and inhibitors also significantly induced and reduced, respectively, cell proliferation/migration/invasion of AR-positive bladder cancer lines, but not AR-knockdown or AR-negative lines, and their growth in xenograft-bearing mice. In both nonneoplastic and neoplastic urothelial cells, NF-κB activators/inhibitors upregulated/downregulated, respectively, AR expression, whereas AR overexpression was associated with increases in the expression levels of NF-κB/p65 and phospho-NF-κB/p65. Thus, NF-κB appeared to be activated in bladder cancer, which was associated with tumor progression. NF-κB activators/inhibitors were also found to modulate tumorigenesis and tumor outgrowth in AR-activated urothelial cells. Accordingly, NF-κB inhibition, together with AR inactivation, has the potential of being an effective chemopreventive and/or therapeutic approach for urothelial carcinoma. Mol Cancer Ther; 17(6); 1303-14. ©2018 AACR.
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Affiliation(s)
- Satoshi Inoue
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
- James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland
- Department of Urology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hiroki Ide
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
- James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland
- Department of Urology, Keio University School of Medicine, Tokyo, Japan
| | - Taichi Mizushima
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
- James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Guiyang Jiang
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York
| | - George J Netto
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
- James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland
- Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama
| | - Momokazu Gotoh
- Department of Urology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hiroshi Miyamoto
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York.
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
- James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland
- Department of Urology, University of Rochester Medical Center, Rochester, New York
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Kashiwagi E, Inoue S, Mizushima T, Chen J, Ide H, Kawahara T, Reis LO, Baras AS, Netto GJ, Miyamoto H. Prostaglandin receptors induce urothelial tumourigenesis as well as bladder cancer progression and cisplatin resistance presumably via modulating PTEN expression. Br J Cancer 2018; 118:213-223. [PMID: 29123257 PMCID: PMC5785746 DOI: 10.1038/bjc.2017.393] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2017] [Revised: 10/04/2017] [Accepted: 10/06/2017] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND We investigated the role of prostaglandin receptors (e.g. prostaglandin E2 receptor 2 (EP2), EP4) and the efficacy of celecoxib in urothelial tumourigenesis and cancer progression. METHODS We performed immunohistochemistry in bladder cancer (BC) tissue microarrays, in vitro transformation assay in a normal urothelial SVHUC line, and western blot/reverse transcription-polymerase chain reaction/cell growth assays in BC lines. RESULTS EP2/EP4 expression was elevated in BCs compared with non-neoplastic urothelial tissues and in BCs from those who were resistant to cisplatin-based neoadjuvant chemotherapy. Strong positivity of EP2/EP4 in non-muscle-invasive tumours or positivity of EP2/EP4 in muscle-invasive tumours strongly correlated with disease progression or disease-specific mortality, respectively. In SVHUC cells, exposure to a chemical carcinogen 3-methylcholanthrene considerably increased and decreased the expression of EP2/EP4 and phosphatase and tensin homologue (PTEN), respectively. Treatment with selective EP2/EP4 antagonist or celecoxib also resulted in prevention in 3-methylcholanthrene-induced neoplastic transformation of SVHUC cells. In BC lines, EP2/EP4 antagonists and celecoxib effectively inhibited cell viability and migration, as well as augmented PTEN expression. Furthermore, these drugs enhanced the cytotoxic activity of cisplatin in BC cells. EP2/EP4 and PTEN were also elevated and reduced, respectively, in cisplatin-resistant BC sublines. CONCLUSIONS EP2/EP4 activation correlates with induction of urothelial cancer initiation and outgrowth, as well as chemoresistance, presumably via downregulating PTEN expression.
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Affiliation(s)
- Eiji Kashiwagi
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Satoshi Inoue
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Taichi Mizushima
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Jinbo Chen
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Hiroki Ide
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Takashi Kawahara
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Leonardo O Reis
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Alexander S Baras
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - George J Netto
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Hiroshi Miyamoto
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642, USA
- Department of Urology, University of Rochester Medical Center, Rochester, NY 14642, USA
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Expression of AR, 5αR1 and 5αR2 in bladder urothelial carcinoma and relationship to clinicopathological factors. Life Sci 2017; 190:15-20. [PMID: 28947209 DOI: 10.1016/j.lfs.2017.09.029] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Revised: 09/21/2017] [Accepted: 09/22/2017] [Indexed: 11/24/2022]
Abstract
AIMS Bladder urothelial carcinoma is increasing in incidence with age and its prognosis could become worse when accompanied with metastasis. Effective treatment of these advanced patients is required and it becomes important to understand its underlying biology of this neoplasm, especially with regard to its biological pathways. A potential proposed pathway is androgen receptor (AR)-mediated intracellular signaling but the details have remained relatively unexplored. MAIN METHODS The expression of AR, 5α-reductase type1 (5αR1) and 5α-reductase type2 (5αR2) were examined in the bladder cancer cell line T24 and surgical pathology specimens. We also evaluated the status of androgen related cell proliferation and migration using the potent, non-aromatizable androgen agonist 5α-dihydrotestosterone (DHT). KEY FINDINGS DHT treatment significantly increased AR mRNA expression level, but not those of 5αR1 and 5αR2 in T24 cells. DHT also suppressed cellular migration with weaker and opposite effects on cell proliferation. A significant inverse correlation was detected between pT stage and AR, 5αR1 and 5αR2 immunoreactivity. SIGNIFICANCE Inverse correlations detected between tumor grade and AR/androgen metabolizing enzyme also suggested that the loss of AR and androgen-producing enzymes could be associated with tumor progression. Effects of DHT on cells also suggest that androgens may regulate cellular behavior.
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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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Sikic D, Breyer J, Hartmann A, Burger M, Erben P, Denzinger S, Eckstein M, Stöhr R, Wach S, Wullich B, Keck B, Wirtz RM, Otto W. High Androgen Receptor mRNA Expression Is Independently Associated with Prolonged Cancer-Specific and Recurrence-Free Survival in Stage T1 Bladder Cancer. Transl Oncol 2017; 10:340-345. [PMID: 28342317 PMCID: PMC5367846 DOI: 10.1016/j.tranon.2017.01.013] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2016] [Revised: 01/24/2017] [Accepted: 01/31/2017] [Indexed: 12/11/2022] Open
Abstract
INTRODUCTION High-risk non-muscle-invasive bladder cancer (NMIBC) remains challenging given the high probability of progression. Given that the androgen receptor (AR) has been discussed as a possible factor in the development and progression of bladder cancer, we investigated the predictive value of AR in stage pT1 NMIBC. MATERIALS AND METHODS We retrospectively analyzed the clinical data and AR mRNA expression in 296 patients with stage pT1 NMIBC who underwent a transurethral resection of the bladder. The mRNA expression of the AR transcript variants 1 (AR1) and 2 (AR2) was measured by reverse transcription quantitative real-time polymerase chain reaction. AR expression was also correlated to KRT5 and KRT20 mRNA expression. RESULTS Kaplan-Meier analysis indicated that high AR1 mRNA expression ≥35.47 is associated with statistically significant better recurrence-free survival (RFS) (P=.0007), progression-free survival (PFS) (P=.0420), and cancer-specific survival (CSS) (P=.0050). Multivariate Cox regression analysis revealed that high AR1 mRNA expression is an independent prognostic marker for RFS (P=.0029) and CSS (P=.0119). Spearman rank correlation revealed a significant positive association between mRNA expression of AR1 and KRT5 (rs: 0.3171, P<.0001) as well as a negative association with multifocal tumors (rs: 0.1478, P<.0109). No association was noted between AR1 expression and tumor grade, concomitant CIS, gender, tumor size, and KRT20 in patients with stage T1 NMIBC. CONCLUSIONS AR mRNA expression can predict RFS and CSS in patients with stage T1 NMIBC. Further studies are necessary to refine the relevance of AR mRNA expression compared with immunohistochemically detectable AR expression.
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Affiliation(s)
- Danijel Sikic
- Department of Urology, University Hospital Erlangen, Erlangen, Germany.
| | - Johannes Breyer
- Department of Urology, University of Regensburg, Regensburg, Germany.
| | - Arndt Hartmann
- Institute of Pathology, University Hospital Erlangen, Erlangen, Germany.
| | - Maximilian Burger
- Department of Urology, University of Regensburg, Regensburg, Germany.
| | - Philipp Erben
- Department of Urology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
| | - Stefan Denzinger
- Department of Urology, University of Regensburg, Regensburg, Germany.
| | - Markus Eckstein
- Institute of Pathology, University Hospital Erlangen, Erlangen, Germany.
| | - Robert Stöhr
- Institute of Pathology, University Hospital Erlangen, Erlangen, Germany.
| | - Sven Wach
- Department of Urology, University Hospital Erlangen, Erlangen, Germany.
| | - Bernd Wullich
- Department of Urology, University Hospital Erlangen, Erlangen, Germany.
| | - Bastian Keck
- Department of Urology, University Hospital Erlangen, Erlangen, Germany.
| | - Ralph M Wirtz
- STRATIFYER Molecular Pathology GmbH, Cologne, Germany.
| | - Wolfgang Otto
- Department of Urology, University of Regensburg, Regensburg, Germany.
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