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Male Genitourinary Tumors: Molecular Mechanisms and Potential Therapeutic Targets
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Male Genitourinary Tumors: Molecular Mechanisms and Potential Therapeutic Targets

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 25 July 2025 | Viewed by 8835

Special Issue Editors

Prof. Dr. Luigi Cormio

E-Mail Website
Guest Editor
Urology and Andrology Unit, Andria Teaching Hospital, University of Foggia, Foggia, Italy
Interests: urology; urogenital diseases; surgery
Special Issues, Collections and Topics in MDPI journals
Dr. Francesca Sanguedolce

E-Mail Website
Guest Editor
Department of Pathology, University of Foggia School of Medicine, 71121 Foggia, Italy
Interests: genitourinary pathology; diagnostic biomarkers; prognostic/predictive biomarkers; digital pathology; emolymphopathology; bladder cancer; prostate cancer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Genitourinary (GU) tumors are common in men of all ages, with prostate cancer and bladder cancer ranking 1st and 4th among the most prevalent tumors worldwide, respectively. Clinically, GU tumors are heterogeneous diseases, carrying either an aggressive outcome with progression and/or metastasis, or an indolent clinical course with low mortality rates. Such heterogeneity is underlined by different genetic/epigenetic events resulting in the initial development and further progression of these tumors. Over the last decades, advances in molecular technologies provided an insight into the pathogenesis of GU tumors, and pointed out possible biomarkers to be used in order to stratify men whose risk to develop tumors with poor outcome and/or not responding to conventional therapeutic options is higher as compared to the general population. Furthermore, some of those biomarkers with prognostic/predictive potential may also play a role as potential therapeutic targets, in light of the recent development of targeted treatments, novel approaches and technologies, and improvements in conventional therapeutic options.  This Special Issue is dedicated to investigating and describing the molecular mechanisms of GU tumorigenesis, and to reporting on novel molecules which can be used as potential therapeutic targets, as well as to broadening the use of established biomarkers. Both reviews and research articles focusing on these topics, expecially those applying findings from basic biology and clinical trials to tools fulfiling unmet clinical needs are welcome.

Prof. Dr. Luigi Cormio
Dr. Francesca Sanguedolce
Guest Editors

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Keywords

  • prostate cancer
  • bladder cancer
  • biomarkers
  • molecular mechanisms
  • therapeutic targets
  • translational research

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Published Papers (5 papers)

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Research

13 pages, 4273 KiB  
Article
Diagnostic and Prognostic Potential of SH3YL1 and NOX4 in Muscle-Invasive Bladder Cancer
by Mingyu Kim, Euihyun Jung, Geehyun Song, Jaeyoung Joung, Jinsoo Chung, Hokyung Seo and Hyungho Lee
Int. J. Mol. Sci. 2025, 26(9), 3959; https://doi.org/10.3390/ijms26093959 - 22 Apr 2025
Viewed by 392
Abstract
Bladder cancer, especially muscle-invasive bladder cancer (MIBC), poses significant treatment challenges due to its aggressive nature and poor prognosis, often necessitating cisplatin-based chemotherapy. While cisplatin effectively reduces tumor burden, its nephrotoxic effects, specifically cisplatin-induced acute kidney injury (AKI), limit its clinical use. This [...] Read more.
Bladder cancer, especially muscle-invasive bladder cancer (MIBC), poses significant treatment challenges due to its aggressive nature and poor prognosis, often necessitating cisplatin-based chemotherapy. While cisplatin effectively reduces tumor burden, its nephrotoxic effects, specifically cisplatin-induced acute kidney injury (AKI), limit its clinical use. This study investigates SH3YL1 as a potential biomarker for bladder cancer progression and AKI. Plasma and urine SH3YL1 levels were measured in bladder cancer patients undergoing cisplatin treatment, showing elevated baseline levels compared to controls, suggesting a link with bladder cancer pathology rather than cisplatin-induced AKI. Functional network and Gene Ontology (GO) enrichment analyses identified SH3YL1’s interactions with NADPH oxidase pathways, particularly NOX family genes, and highlighted its roles in cell adhesion, migration, and cytoskeletal organization—processes critical for tumor invasiveness. Notably, SH3YL1 and NOX4 expression were significantly higher in MIBC than in non-muscle-invasive bladder cancer (NMIBC), with a strong correlation between SH3YL1 and NOX4 (r = 0.62) in MIBC, suggesting a subtype-specific interaction. Kaplan–Meier survival analysis using The Cancer Genome Atlas bladder cancer (TCGA-BLCA) data further demonstrated that low SH3YL1 expression is significantly associated with poor overall and disease-specific survival in MIBC patients, reinforcing its role as a prognostic biomarker. In conclusion, SH3YL1 is a promising biomarker for identifying the invasive characteristics of MIBC and predicting patient outcomes. These findings underscore the importance of SH3YL1–NOX4 pathways in MIBC and suggest the need for further research into targeted biomarkers for bladder cancer progression and cisplatin-induced AKI to improve patient outcomes in high-risk cases. Full article
(This article belongs to the Special Issue Male Genitourinary Tumors: Molecular Mechanisms and Potential Therapeutic Targets)
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12 pages, 4712 KiB  
Article
Latrophilins as Downstream Effectors of Androgen Receptors including a Splice Variant, AR-V7, Induce Prostate Cancer Progression
by Yuki Teramoto, Mohammad Amin Elahi Najafi, Takuo Matsukawa, Adhya Sharma, Takuro Goto and Hiroshi Miyamoto
Int. J. Mol. Sci. 2024, 25(13), 7289; https://doi.org/10.3390/ijms25137289 - 2 Jul 2024
Cited by 2 | Viewed by 1735
Abstract
Latrophilins (LPHNs), a group of the G-protein–coupled receptor to which a spider venom latrotoxin (LTX) is known to bind, remain largely uncharacterized in neoplastic diseases. In the present study, we aimed to determine the role of LPHNs in the progression of prostate cancer. [...] Read more.
Latrophilins (LPHNs), a group of the G-protein–coupled receptor to which a spider venom latrotoxin (LTX) is known to bind, remain largely uncharacterized in neoplastic diseases. In the present study, we aimed to determine the role of LPHNs in the progression of prostate cancer. We assessed the actions of LPHNs, including LPHN1, LPHN2, and LPHN3, in human prostate cancer lines via their ligand (e.g., α-LTX, FLRT3) treatment or shRNA infection, as well as in surgical specimens. In androgen receptor (AR)-positive LNCaP/C4-2/22Rv1 cells, dihydrotestosterone considerably increased the expression levels of LPHNs, while chromatin immunoprecipitation assay revealed the binding of endogenous ARs, including AR-V7, to the promoter region of each LPHN. Treatment with α-LTX or FLRT3 resulted in induction in the cell viability and migration of both AR-positive and AR-negative lines. α-LTX and FLRT3 also enhanced the expression of Bcl-2 and phosphorylated forms of JAK2 and STAT3. Meanwhile, the knockdown of each LPHN showed opposite effects on all of those mediated by ligand treatment. Immunohistochemistry in radical prostatectomy specimens further showed the significantly elevated expression of each LPHN in prostate cancer, compared with adjacent normal-appearing prostate, which was associated with a significantly higher risk of postoperative biochemical recurrence in both univariate and multivariable settings. These findings indicate that LPHNs function as downstream effectors of ARs and promote the growth of androgen-sensitive, castration-resistant, or even AR-negative prostate cancer. Full article
(This article belongs to the Special Issue Male Genitourinary Tumors: Molecular Mechanisms and Potential Therapeutic Targets)
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28 pages, 14254 KiB  
Article
Identification and Validation of Tumor Microenvironment-Associated Signature in Clear-Cell Renal Cell Carcinoma through Integration of DNA Methylation and Gene Expression
by Zijian Ye, Jialiang Xu, Xin Zhang, Yifan Zhang, Deyana Ivanova, Weiyu Lu, Jianning Zhang, Fangfang Li, Xuemei Chen, Yingxiong Wang, Meijiao Wang and Biao Xie
Int. J. Mol. Sci. 2024, 25(12), 6792; https://doi.org/10.3390/ijms25126792 - 20 Jun 2024
Viewed by 1970
Abstract
The tumor microenvironment (TME) is crucial in tumor development, metastasis, and response to immunotherapy. DNA methylation can regulate the TME without altering the DNA sequence. However, research on the methylation-driven TME in clear-cell renal cell carcinoma (ccRCC) is still lacking. In this study, [...] Read more.
The tumor microenvironment (TME) is crucial in tumor development, metastasis, and response to immunotherapy. DNA methylation can regulate the TME without altering the DNA sequence. However, research on the methylation-driven TME in clear-cell renal cell carcinoma (ccRCC) is still lacking. In this study, integrated DNA methylation and RNA-seq data were used to explore methylation-driven genes (MDGs). Immune scores were calculated using the ESTIMATE, which was employed to identify TME-related genes. A new signature connected with methylation-regulated TME using univariate, multivariate Cox regression and LASSO regression analyses was developed. This signature consists of four TME-MDGs, including AJAP1, HOXB9, MYH14, and SLC6A19, which exhibit high methylation and low expression in tumors. Validation was performed using qRT-PCR which confirmed their downregulation in ccRCC clinical samples. Additionally, the signature demonstrated stable predictive performance in different subtypes of ccRCC. Risk scores are positively correlated with TMN stages, immune cell infiltration, tumor mutation burden, and adverse outcomes of immunotherapy. Interestingly, the expression of four TME-MDGs are highly correlated with the sensitivity of first-line drugs in ccRCC treatment, especially pazopanib. Molecular docking indicates a high affinity binding between the proteins and pazopanib. In summary, our study elucidates the comprehensive role of methylation-driven TME in ccRCC, aiding in identifying patients sensitive to immunotherapy and targeted therapy, and providing new therapeutic targets for ccRCC treatment. Full article
(This article belongs to the Special Issue Male Genitourinary Tumors: Molecular Mechanisms and Potential Therapeutic Targets)
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11 pages, 2276 KiB  
Article
An Antibody of the Secreted Isoform of Disintegrin and Metalloprotease 9 (sADAM9) Inhibits Epithelial–Mesenchymal Transition and Migration of Prostate Cancer Cell Lines
by Yura Jotatsu, Shain-Ying Sung, Ming-Heng Wu, Shunya Takeda, Yuto Hirata, Koki Maeda, Shiuh-Bin Fang, Kuan-Chou Chen and Katsumi Shigemura
Int. J. Mol. Sci. 2024, 25(12), 6646; https://doi.org/10.3390/ijms25126646 - 17 Jun 2024
Viewed by 1610
Abstract
Prostate cancer (PC) is the most common cancer diagnosed in men worldwide. Currently, castration-resistant prostate cancer (CRPC), which is resistant to androgen deprivation therapy, has a poor prognosis and is a therapeutic problem. We investigated the antitumor effects on PC of an antibody [...] Read more.
Prostate cancer (PC) is the most common cancer diagnosed in men worldwide. Currently, castration-resistant prostate cancer (CRPC), which is resistant to androgen deprivation therapy, has a poor prognosis and is a therapeutic problem. We investigated the antitumor effects on PC of an antibody neutralizing secreted disintegrin and metalloproteinase domain-containing protein 9 (sADAM9), which is a blood-soluble form. We performed proliferation assays, wound healing assays, invasion assays, Western blot (WB), and an in vivo study in which a sADAM9 neutralizing antibody was administered intratumorally to PC-bearing mice. In invasion assays, the sADAM9 neutralizing antibody significantly inhibited invasion in all cell lines (TRAMP-C2: p = 0.00776, LNCaP: p = 0.000914, PC-3: p = 0.0327, and DU145: p = 0.0254). We examined epithelial–mesenchymal transition (EMT) markers, one of the metastatic mechanisms, in WB and showed downregulation of Slug in TRAMP-C2, LNCaP, and DU145 and upregulation of E-cadherin in TRAMP-C2 and PC-3 by sADAM9 neutralization. In mouse experiments, the sADAM9 neutralizing antibody significantly suppressed tumor growth compared to controls (1.68-fold in TRAMP-C2, 1.89-fold in LNCaP, and 2.67-fold in PC-3). These results suggested that the sADAM9 neutralizing antibody inhibits invasion, migration, and tumor growth in PC. Previous studies examined the anti-tumor effect of knockdown of total ADAM9 or sADAM9, but this study used the new technology of neutralizing antibodies for sADAM9. This may be novel because there was no animal study using a neutralizing antibody for sADAM9 to see the relationship between ADAM9 expression and prostate cancer. Full article
(This article belongs to the Special Issue Male Genitourinary Tumors: Molecular Mechanisms and Potential Therapeutic Targets)
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11 pages, 14502 KiB  
Article
The Reduction of PSMB4 in T24 and J82 Bladder Cancer Cells Inhibits the Angiogenesis and Migration of Endothelial Cells
by Yi-Hsuan Lin, Tzu-Min Chen, Yu-Ling Tsai, Wen-Chiuan Tsai, Hisao-Hsien Wang, Ying Chen and Sheng-Tang Wu
Int. J. Mol. Sci. 2024, 25(10), 5559; https://doi.org/10.3390/ijms25105559 - 20 May 2024
Cited by 2 | Viewed by 2282
Abstract
Bladder cancer (BC) is a malignant tumor of the urinary system with high mortality and recurrence rates. Proteasome subunit type 4 (PSMB4) is highly expressed and has been identified as having oncogenic properties in a variety of cancer types. This study aimed to [...] Read more.
Bladder cancer (BC) is a malignant tumor of the urinary system with high mortality and recurrence rates. Proteasome subunit type 4 (PSMB4) is highly expressed and has been identified as having oncogenic properties in a variety of cancer types. This study aimed to explore the effect of PSMB4 knockdown on the survival, migration, and angiogenesis of human bladder cancer cells with different degrees of malignancy. We analyzed the effects of PSMB4 knockdown in bladder cancer cells and endothelial cells in the tumor microenvironment. PSMB4 was highly expressed in patients with low- and high-grade urothelial carcinoma. Inhibition of PSMB4 reduced protein expression of focal adhesion kinase (FAK) and myosin light chain (MLC), leading to reduced migration. Furthermore, the suppression of PSMB4 decreased the levels of vascular endothelial factor B (VEGF-B), resulting in lower angiogenic abilities in human bladder cancer cells. PSMB4 inhibition affected the migratory ability of HUVECs and reduced VEGFR2 expression, consequently downregulating angiogenesis. In the metastatic animal model, PSMB4 knockdown reduced the relative volumes of lung tumors. Our findings suggest the role of PSMB4 as a potential target for therapeutic strategies against human bladder cancer. Full article
(This article belongs to the Special Issue Male Genitourinary Tumors: Molecular Mechanisms and Potential Therapeutic Targets)
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