ADAM12 promotes clear cell renal cell carcinoma progression and triggers EMT via EGFR/ERK signaling pathway.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is a major worldwide health problem due to its high prevalence and mortality rate. A disintegrin and metalloproteinase 12 (ADAM12) is aberrantly expressed in various cancers and plays an important role in tumor progression. However, its explicit effect and molecular mechanism in ccRCC remain unclear. METHODS: We investigated the dysregulation of ADAM12 in ccRCC through public databases and bioinformatics analyses. The expression of ADAM12 was further verified in ccRCC tissues by RT-qPCR and immunohistochemistry (IHC). The relationship between ADAM12 expression and clinicopathological characteristics was analyzed statistically. The effects of ADAM12 on the proliferation, migration and invasion of ccRCC cells were examined by in vitro and in vivo experiments. RESULTS: ADAM12 was significantly upregulated in ccRCC tissues and associated with poor prognosis in ccRCC patients. ADAM12 promoted ccRCC cell proliferation, migration and invasion in vitro and the growth of subcutaneous tumors in vivo. Knockdown of ADAM12 successfully suppressed its oncogenic function. Mechanistically, its overexpression induced epithelial-mesenchymal transition (EMT) by downregulating E-cadherin and upregulating N-cadherin and Snail. Moreover, ADAM12 participated in the epidermal growth factor receptor (EGFR) pathway and activated the downstream signal ERK1/2 by shedding the EGFR ligand, thereby upregulating target genes including c-Myc, enhancing cell survival and invasion ability, and promoting tumor progression, metastasis and the induction of EMT. CONCLUSIONS: High expression of ADAM12 induced EMT and promoted cell proliferation, migration, and invasion by activating the EGFR/ERK signaling pathway in ccRCC.

HMGN5 knockdown sensitizes prostate cancer cells to ionizing radiation.

BACKGROUND: High Mobility Group N (HMGN) proteins are a family of chromatin structural proteins that specifically bind to nucleosome core particles. HMGN5 is a novel and characteristic member of the HMGN protein family. We have previously found that HMGN5 is upregulated in prostate cancer and its downregulation had been demonstrated to induce apoptosis and G2-M cell cycle arrest. METHODS: The radiosensitization effect of HMGN5 knockdown on PC3 and DU145 cells was assessed using clonogenic assay, flow cytometry, and comet assay. The DNA double-strand break (DSB) repair kinetics of HMGN5 knockdown and control cells after radiation exposure was evaluated using immunocytofluorescence. The mitochondrial reactive oxygen species (ROS) levels were estimated using Dihydrorhodamine 123 (DHR 123) probes. Expression of mitochondrial antioxidant MnSOD was measured by real-time PCR and Western blot. The expression of antiapoptotic proteins Bcl-2 and Bcl-xL as well as cleavage of caspase-3, caspase-9, and PARP were also measured using Western blot. RESULTS: HMGN5 knockdown cells exhibit decreased clonogenic survival and increased apoptosis rate in response to 2-8 Gy ionizing radiation (IR). Loss of HMGN5 does not affect the DSB repair kinetics after radiation exposure. HMGN5 knockdown cells demonstrated increased mitochondrial ROS level and suppressed induction of MnSOD upon radiation compared with control cells upon radiation. Further, MnSOD knockdown resulted in inhibited cell viability as well as increased mitochondrial ROS level and apoptosis upon radiation in PC3 and DU145 cells. Finally, HMGN5 knockdown cells showed significantly decreased levels of antiapoptotic proteins Bcl-2 and Bcl-xL as well as increased cleavage of caspase-3, caspase-9, and PARP compared with control cells after radiation. CONCLUSIONS: HMGN5 knockdown sensitizes prostate cancer cells to ionizing radiation, and the radiosensitization effect may be partially mediated through suppressed induction of MnSOD and enhanced activation of apoptosis pathway in response to IR.

High expression of KPNA2 defines poor prognosis in patients with upper tract urothelial carcinoma treated with radical nephroureterectomy.

BACKGROUND: To analyze the expression of karyopherin alpha 2 (KPNA2) in upper tract urothelial carcinoma (UTUC) and to investigate whether the KPNA2 expression provides additional prognostic information following radical nephroureterectomy (RNU). METHODS: A tissue microarray (TMA) containing samples from 176 patients with UTUC who underwent RNU at our institute was analyzed for KPNA2 expression using immunohistochemistry. KPNA2 expression in normal urothelial cell line and urothelial carcinoma cell lines was evaluated by western blot analysis. Using RNA interference in vitro, the effects of KPNA2 inhibition on cellular viability, migration and apoptosis were determined. RESULTS: KPNA2 expression was significantly upregulated in the UTUC samples compared with the adjacent normal urothelial tissues. High KPNA2 immunoreactivity was identified as a predictor of bladder recurrence (hazard ratio [HR]: 2.017, 95% CI 1.13-3.61, p = 0.018), poor disease-free survival (DFS, HR: 2.754, 95% CI 1.68-4.51, p = 0.001) and poor overall survival (OS, HR: 4.480, 95% CI 1.84-10.89, p = 0.001) for patients with UTUC after RNU. Furthermore, high KPNA2 immunoreactivity was independent of the conventional predictive factors in a multivariate analysis. Additional in vitro experiments revealed that KPNA2 expression was higher in urothelial carcinoma cell lines than in normal urothelial cell line. KPNA2 inhibition with a specific siRNA decreased cell viability and migration and increased apoptosis in urothelial carcinoma cell lines. CONCLUSIONS: KPNA2 is a novel independent prognostic marker for bladder recurrence, DFS and OS of UTUC patients who have undergone RNU. Moreover, these data suggest that KPNA2 may be a promising therapeutic target for UTUC.

Let-7d suppresses growth, metastasis, and tumor macrophage infiltration in renal cell carcinoma by targeting COL3A1 and CCL7.

BACKGROUND: MicroRNAs are endogenous small noncoding RNAs that are functionally involved in numerous critical cellular processes including tumorigenesis. Data mining using a microRNA array database suggested that let-7d microRNA may be associated with renal cell carcinoma (RCC) malignant progression. Here, we performed further analyses to determine whether let-7d is functionally linked to RCC malignancy. METHODS: Quantitative real-time PCR was used to determine the level of mature let-7d in RCC clinical specimens and its correlation with clinicopathological data. Immunohistochemical staining was conducted to characterize the stroma of RCC. Let-7d overexpressing RCC cell lines combined with mouse models bearing cell-derived xenografts and patient-derived xenografts were used to assess the functional role of let-7d in vitro and in vivo. RESULTS: Downregulation of let-7d in clinical RCC samples was associated with advanced tumor grade and T stage and increased vascular invasion. An inverse relationship between let-7d expression and macrophage infiltration was found in clinical RCC samples. Functional studies indicated that ectopic expression of let-7d significantly inhibited RCC cell proliferation, migration, and peripheral blood monocyte (PBMC) recruitment in vitro, as well as tumor growth, metastasis, and tumor macrophage infiltration in vivo. In silico analysis and subsequent experimental validation confirmed collagen, type III, alpha 1 (COL3A1) and C-C subfamily chemokine member CCL7 as direct let-7d target genes. The addition of COL3A1 and CCL7 counteracted the inhibitory effects of let-7d on RCC cell proliferation, migration, and PBMC recruitment. The inhibition of let-7d increased cell proliferation, migration, and PBMC recruitment by the enhanced expression of COL3A1 and CCL7 genes in vitro. The mRNA levels of COL3A1 and CCL7 were inversely correlated with let-7d level in RCC clinical specimens. CONCLUSIONS: These results suggest that let-7d may suppress RCC growth, metastasis, and tumor macrophage infiltration at least partially through targeting COL3A1 and CCL7.

Resiniferatoxin for treatment of lifelong premature ejaculation: a preliminary study.

OBJECTIVES: To evaluate the efficacy of resiniferatoxin in the treatment of patients with lifelong premature ejaculation. METHODS: A total of 41 outpatients (mean age 26.14 ± 4 years) with premature ejaculation completed the present study. They were randomly separated into the resiniferatoxin group and the placebo group. The resiniferatoxin group included 11 patients with redundant prepuce and 10 patients without redundant prepuce, whereas the placebo group contained 10 patients with redundant prepuce and 10 patients without. For the treatment, the glans were respectively soaked in 30 mL of resiniferatoxin with a concentration of 100 nmol/L or 10% alcohol solution for 30 min before sexual intercourse. Clinical efficacy was assessed by using the Chinese Index of Sexual Function for Premature Ejaculation-5 and the intravaginal ejaculation latency time before or 4 weeks after the treatment. The side-effects were also evaluated. RESULTS: In the resiniferatoxin group, the effective rate of patients with redundant prepuce was 63.6%, and both the intravaginal ejaculation latency time and Chinese Index of Sexual Function for Premature Ejaculation-5 significantly increased (P < 0.05). However, the effective rate of patients without redundant prepuce was 20%, and there were no significant changes of their intravaginal ejaculation latency time and Chinese Index of Sexual Function for Premature Ejaculation-5 before and after the resiniferatoxin treatment (P > 0.05). The total effective rate of patients treated with resiniferatoxin was 42.9%. In the placebo group, the effective rate of patients with or without redundant prepuce was 20% and 10%, respectively. The total effective rate of patients treated with placebo was 15%, and there were no significant changes of their intravaginal ejaculation latency time and Chinese Index of Sexual Function for Premature Ejaculation-5 before and after the placebo treatment (P > 0.05). The side-effects included a slight burning sensation for the glans penis and dysuria. CONCLUSIONS: These preliminary results show that resiniferatoxin might be suitable for treating patients with lifelong premature ejaculation and particularly those with redundant prepuce.

Chronic scrotal pain caused by Mild Epididymitis:Report of a series of 44 cases.

OBJECTIVES: Patients with idiopathic chronic scrotal pain are challenging to both the general practioner and urologist. In this study, we tried to recognize mild epididymitis as an underrecogniczed cause of idiopathic chronic scrotal pain. Methods : We described a consecutive series of 44 patients with idiopathic chronic scrotal pain characterized by mild scrotal pain, mild to moderate tenderness of epididymis without abnormal swelling of epididymis. We obtained a detailed history and physical examination along with routine urinalysis and Doppler ultrasound to identify the characteristics of this new clinical entity. Results : A consecutive series of 44 patients who were primarily diagnosed as "idiopathic chronic scrotal pain" came to our hospital. All had the sign of mild to moderate tenderness on the affected epididymis without epididymis enlargement. Doppler ultrasound showed the affected epididymis with normal size and no abnormal change. We treated them with antibiotics orally along with cessation of strenuous activity and all fully recovered from scrotal pain. CONCLUSION: In this study, we recognized mild epididymitis as an underrecogniczed cause of idiopathic chronic scrotal pain. It was characterized by mild scrotal pain, mild to moderate tenderness of epididymis without abnormal enlargement of epididymis.

The relationship between oxidative balance score and erectile dysfunction in the U.S. male adult population.

Oxidative stress strongly influences the pathophysiology of erectile dysfunction (ED). In this study, we used the oxidative balance score (OBS), a composite index, to measure the effects of oxidative stress triggered by diet and lifestyle factors. Here, we conducted a cross-sectional study to determine the statistical relationship between OBS and ED among adult males in the U.S. The data from 3318 participants in the National Health and Nutrition Examination Survey (NHANES) 2001-2004 were analyzed. Weighted logistic regression was used to correct for confounding factors and acquire nationwide representative estimates. Generalized additive modeling was used to explore the nonlinear relationship. We also supplemented subgroup and sensitivity analysis to examine the robustness of the main results. Multivariate logistic regression indicated a consistent negative linear association between OBS and ED across all participants [OR (95% CI) = 0.96 (0.94, 0.98)]. After categorizing OBS into tertiles, participants in the highest tertile had 43% lower odds of having ED than those in the lowest tertile [OR (95% CI) = 0.57 (0.37, 0.87)]. The generalized additive model also visualized the linear trend of this association. Furthermore, this linear relationship remained relatively consistent, regardless of whether subgroup or sensitivity analyses were performed. Our findings suggest that adopting a lifestyle and diet pattern that promotes favorable OBS may effectively protect against the development of ED, regardless of the underlying causes.

ITM2A inhibits the progression of bladder cancer by downregulating the phosphorylation of STAT3.

Bladder cancer stands as one of the prevalent malignancies in urological clinics, highlighting the pressing need to uncover prognostic or therapeutic avenues. ITM2A, a transmembrane protein, has been identified as a suppressor in tumor progression recently. Our study underscored a significant correlation between low ITM2A expression in bladder cancer tissues and high tumor grade, AJCC stage, and poor overall survival time. Additionally, our findings demonstrated that reinstating ITM2A expression impeded cell proliferation, migration, and invasion, while conversely, its suppression enhanced these malignant behaviors. Furthermore, we elucidated that ITM2A could suppress malignant phenotypes of bladder cancer cells via inhibiting activation of the STAT3 induced by IL-6. In conclusion, our research unveiled the mechanistic role of ITM2A in inhibiting tumor progression, shedding light on its potential as a prognostic predictor and therapeutic target in bladder cancer management.

Association between life's essential 8 and male biochemical androgen deficiency: evidence from NHANES 2013-2016.

Purpose: To evaluate the association of Life's Essential 8 (LE8) and its subscales with male biochemical androgen deficiency (MBAD) and total testosterone based on the data from the national health and nutrition examination survey (NHANES) database. Methods: Data of males aged 20 years or older from NHANES of 2013-2016 were extracted. LE8 score was calculated based on American Heart Association definitions. Total testosterone (TT) values were measured in NHANES using precise isotope dilution liquid chromatography. MBAD was defined as serum TT of <300 ng/dL. Univariate and multivariable analyses were conducted. Propensity score matching (PSM) and weighted regression after matching were added as sensitivity analyses. The generalized additive model, smooth curve fitting, and the recursive algorithm were used to determine the potential inflection points. Piecewise regression models with log-likelihood ratio test were used to quantify nonlinear effects. Results: A total of 3094 participants who were males and aged 20 years or above were included. Out of them, 805 males were diagnosed with MBAD. After adjusting the confounders in the multivariable model, LE8 was independently associated with MBAD (OR 0.96, P < 0.001) and TT (ß 2.7, P < 0.001). The association remained robust even after PSM. The non-linear relationship of LE8 behaviors score with MBAD and TT was revealed. Conclusion: LE8 was an independent protective factor of MBAD and a feasible approach to promote male endocrine sexual function.

Bladder Cancer in Exosomal Perspective: Unraveling New Regulatory Mechanisms.

Bladder cancer, a prevalent malignant neoplasm of the urinary tract, exhibits escalating morbidity and mortality rates. Current diagnosis standards rely on invasive and costly cystoscopy and histopathology, underscoring the urgency for non-invasive, high-throughput, and cost-effective novel diagnostic techniques to ensure timely detection and standardized treatment. Recent years have witnessed the rise of exosome research in bladder cancer studies. Exosomes contain abundant bioactive molecules that can help elucidate the intricate mechanisms underlying bladder cancer pathogenesis and metastasis. Exosomes hold potential as biomarkers for early bladder cancer diagnosis while also serving as targeted drug delivery vehicles to enhance treatment efficacy and mitigate adverse effects. Furthermore, exosome analyses offer insights into the complex molecular signaling networks implicated in bladder cancer progression, revealing novel therapeutic targets. This review provides a comprehensive overview of prevalent exosome isolation techniques and highlights the promising clinical utility of exosomes in both diagnostic and therapeutic applications in bladder cancer management.

Identification of ATP6V0A4 as a potential biomarker in renal cell carcinoma using integrated bioinformatics analysis.

Clear cell renal cell carcinoma (ccRCC) is the most common pathological type of renal cancer, and is associated with a high mortality rate, which is related to high rates of tumor recurrence and metastasis. The aim of the present study was to identify reliable molecular biomarkers with high specificity and sensitivity for ccRCC. A total of eight ccRCC-related expression profiles were downloaded from Gene Expression Omnibus for integrated bioinformatics analysis to screen for significantly differentially expressed genes (DEGs). Reverse transcription-quantitative (RT-q)PCR, western blotting and immunohistochemistry staining assays were performed to evaluate the expression levels of candidate biomarkers in ccRCC tissues and cell lines. In total, 255 ccRCC specimens and 165 adjacent normal kidney specimens were analyzed, and 344 significant DEGs, consisting of 115 upregulated DEGs and 229 downregulated DEGs, were identified. The results of Gene Ontology analysis suggested a significant enrichment of DEGs in 'organic anion transport' and 'small molecule catabolic process' in biological processes, in 'apical plasma membrane' and 'apical part of the cell' in cell components, and in 'anion transmembrane transporter activity' and 'active transmembrane transporter activity' in molecular functions. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis indicated that the DEGs were significantly enriched in the 'phagosome', the 'PPAR signaling pathway', 'complement and coagulation cascades', the 'HIF-1 signaling pathway' and 'carbon metabolism'. Next, 7 hub genes (SUCNR1, CXCR4, VCAN, CASR, ATP6V0A4, VEGFA and SERPINE1) were identified and validated using The Cancer Genome Atlas database. Survival analysis showed that low expression of ATP6V0A4 was associated with a poor prognosis in patients with ccRCC. Additionally, received operating characteristic curves indicated that ATP6V0A4 could distinguish ccRCC samples from normal kidney samples. Furthermore, RT-qPCR, western blotting and immunohistochemistry staining results showed that ATP6V0A4 was significantly downregulated in ccRCC tissues and cell lines. In conclusion, ATP6V0A4 may be involved in tumor progression and regarded as a potential therapeutic target for the recurrence and metastasis of ccRCC.

Renal pseudoaneurysm after holmium laser lithotripsy with flexible ureteroscopy: an unusual case report and literature review.

Pseudoaneurysms of the renal arteries are caused by focal rupture or perforation of the arterial wall, resulting in local bleeding. Such pseudoaneurysms can be observed in conditions such as nodular polyarteritis, penetrating or closed renal injury, and medically induced injuries (such as renal puncture biopsy, percutaneous nephrostomy, or partial nephrectomy). Flexible ureteroscopy (FURS) is performed entirely through the urethra to prevent potentially severe kidney damage. Because of this, almost no renal parenchymal hemorrhage occurs after FURS laser lithotripsy. Only four cases had been documented in the literature as of December 2022. In this report, we describe a 53-year-old man with a history of recurrent kidney stones who underwent FURS laser lithotripsy for bilateral kidney stones. The procedure was smoothly performed, and no active bleeding occurred. However, the patient developed recurrent macroscopic hematuria after discharge from the hospital, and renal angiography revealed a pseudoaneurysm in the distal right kidney. The pseudoaneurysm was treated with selective arterial embolization. Serious complications of FURS surgery are rare, particularly the formation of pseudoaneurysms. We report the present case to bring this potential complication to the attention of urologists.

[Progress in home uroflowmetry in evaluation of lower urinary tract symptoms in patients].

Uroflowmetry is the most widely used non-invasive urodynamic tool for most patients with suspected lower urinary tract dysfunction. Home uroflowmetry can produce multiple representative flow readings in adequate privacy condition when patients feel a normal desire. Because of its advantages of decreasing variability, describing circadian rhythms and combating problems inherent to clinic-based measurements, it can improve diagnostic accuracy and predictive value. Further studies are required to confirm quantitative data of patient's preferences and to measure cost-benefit of home uroflowmetry.

SMARCC1 Enters the Nucleus via KPNA2 and Plays an Oncogenic Role in Bladder Cancer.

Background: SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin subfamily C member 1 (SMARCC1), a component of the SWI/SNF complex, is thought to be an oncogene in several kinds of cancer. Materials and methods: The potential interaction between SMARCC1 and KPNA2 was inquired by Spearman's correlation analysis, immunofluorescence staining and co-immunoprecipitation (Co-IP) assays. The immunohistochemistry staining, RT-PCR and western blot assay were taken for determining the expression levels of SMARCC1. And CCK-8, transwell assay, cell apoptosis assay, cell cycle analysis and subcutaneous tumor model were conducted to explore the role of SMARCC1 in carcinogenesis of bladder cancer. Results: In our experiments, Spearman's correlation analysis, immunofluorescence staining and co-immunoprecipitation (Co-IP) assays showed that SMARCC1 interacted with KPNA2, and after knockdown of KPNA2, Nup50 and Nup153, the nuclear content of SMARCC1 decreased while the amount of SMARCC1 protein remaining in the cytoplasm increased, indicating that SMARCC1 could be transported into the nucleus via KPNA2 and thus acted as an oncogene. We found that both the mRNA and protein expression levels of SMARCC1 were increased in bladder cancer, and increased SMARCC1 expression was significantly associated with a higher T stage and poorer prognosis in bladder cancer patients. Knockdown of SMARCC1 slowed the growth of the two tested cell lines and clearly arrested the cell cycle at the G0/G1 phase checkpoint. Moreover, the migratory ability was significantly decreased and the number of apoptotic cells was increased. Conclusion: On the whole, our results demonstrate KPNA2, Nup50 and Nup153 regulate the process of SMARCC1 nuclear translocation in BC. SMARCC1 may be a competent candidate as a diagnostic and therapeutic target for BC. Further studies are required to research the mechanism and assess the role of SMARCC1 in vivo.

FAM107A as a Tumor Suppressor in Bladder Cancer Inhibits Cell Proliferation, Migration, and Invasion.

OBJECTIVE: Bladder cancer (BC) is the most common cancer in urinary system. Recently, the function of family with sequence similarity 107 member A (FAM107A) has been reported in several carcinomas. This study aimed to reveal the potential role of FAM107A in bladder cancer. METHODS: Bioinformatics analysis was performed to assess the expression level of FAM107A in BC tissues and adjacent tumor-free bladder tissues. The results were confirmed by quantitative real-time polymerase chain reaction (RT-qPCR), western blot and immunohistochemistry staining in BC tissues and adjacent tumor-free bladder tissues as well as BC cell lines. In addition, plasmid was constructed to increase FAM107A protein level in BC cell lines. The effect of FM107A on cell growth, cell migration and invasion were analyzed by CCK8 assay, wound healing assay and transwell-invasion assay. RESULTS: The data showed that FAM107A was remarkably down-regulated in bladder cancer tissues and bladder cancer cell lines. Besides, low FAM107A expression was associated with high tumor grade of patients with bladder cancer. Moreover, the restoration of FAM107A remarkably suppressed the cell growth, migration, and invasion of BC cells. CONCLUSION: In summary, FAM107A might serve as a tumor suppressor which inhibits BC cell proliferation, migration, and invasion. This study suggests that FAM107A can be a candidate new diagnostic marker and possible therapeutic target gene of bladder cancer.

FAM64A is an androgen receptor-regulated feedback tumor promoter in prostate cancer.

Endocrine therapy for prostate cancer (PCa) mainly inhibits androgen receptor (AR) signaling, due to increased androgen synthesis and AR changes, PCa evolved into castration-resistant prostate cancer (CRPC). The function of Family With Sequence Similarity 64 Member A (FAM64A) and its association with prostate cancer has not been reported. In our research, we first reported that FAM64A is up-regulated and positively associated with poor prognosis of patients with prostate cancer (PCa) by TCGA database and immunohistochemistry staining. Moreover, knockdown of FAM64A significantly suppressed the proliferation, migration, invasion, and cell cycle of PCa cells in vitro. Mechanistically, FAM64A expression was increased by dihydrotestosterone (DHT) through direct binding of AR to FAM64A promoter, and notably promoted the proliferation, migration, invasion, and cell cycle of androgen-dependent cell line of PCa. In addition, abnormal expression of FAM64A affects the immune and interferon signaling pathway of PCa cells. In conclusion, FAM64A was up-regulated by AR through directly binding to its specific promoter region to promote the development of PCa, and was associated with the immune mechanism and interferon signaling pathway, which provided a better understanding and a new potential for treating PCa.

Multilocular cystic renal cell carcinoma: A case report and review of the literature.

Multilocular cystic renal cell carcinoma (MCRCC), which exhibits low-stage and low-grade characteristics, is a special type of RCC. MCRCC is extremely rare and generally develops at ages >50 years. We herein report a case of MCRCC in a 28-year-old man, which, to the best of our knowledge, is the youngest case reported worldwide to date. The patient presented with irritative bladder symptoms for 1 year. Dynamic enhanced computed tomography (CT) imaging revealed a mass with inhomogeneous enhancement in the left kidney, with a rich blood supply. B-ultrasonography also revealed a renal protruding mass. As the mass was highly suspicious to be a malignant tumor, laparoscopic radical nephrectomy was performed and MCRCC was definitively diagnosed by pathological examination. The patient has been regularly followed up for 6 months, without complications or disease recurrence.