Relevance of A Disintegrin and Metalloproteinase Domain-Containing (ADAM)9 Protein Expression to Bladder Cancer Malignancy.

We evaluated the effect of A Disintegrin and Metalloproteinase Domain-Containing (ADAM)9 protein on exacerbation in bladder cancer KK47 and T24. First, we knocked down ADAM9 and investigated cell proliferation, migration, cell cycle, and the epithelial-mesenchymal transition (EMT)-related proteins expression in vitro. We then investigated the expression level of ADAM9 in clinical urine cytology samples and the Cancer Genome Atlas (TCGA) data. Cell proliferation was significantly reduced in both cell lines after ADAM9 knockdown. In the cell-cycle assay, the percentage of G0/G1 cells was significantly increased in ADAM9 knockdown T24. Migration of T24 was more strongly suppressed than KK47. The expression level of EMT-related proteins suggested that EMT was suppressed in ADAM9 knockdown T24. TCGA analysis revealed that ADAM9 mRNA expression was significantly higher in stage IV and high-grade cancer than in other stages and low-grade cancer. Moreover, in the gene expression omnibus (GEO) study, bladder cancer with surrounding carcinoma and invasive carcinoma showed significantly high ADAM9 mRNA expression. We found that ADAM9 knockdown suppressed cell proliferation and migration in bladder cancer and that high-grade bladder cancer is correlated with higher expression of ADAM9.

The ADAM9/UBN2/AKR1C3 axis promotes resistance to androgen-deprivation in prostate cancer.

Metastatic and castration-resistant disease is a fatal manifestation of prostate cancer (PCa). The mechanism through which resistance to androgen deprivation in PCa is developed remains largely unknown. Our understanding of the tumor microenvironment (TME) and key signaling pathways between tumors and their TME is currently changing in light of the generation of new knowledge with regard to cancer progression. A disintegrin and metalloproteinase domain-containing protein 9 (ADAM9) is a membranous bridge forming cell-cell and cell-matrix connections that regulate tumor aggressiveness and metastasis. However, it is not known whether ADAM9 expressed in the TME contributes to the CRPC phenotype. In this study, we aimed to investigate the expression patterns of ADAM9 in prostate cancer-associated fibroblasts (CAFs). We also intended to elucidate the effects of both stromal cell- and cancer cell-derived ADAM9 on the progression of CRPC and the implicated molecular pathways. By using both clinical specimens and cell lines, we herein showed that unlike the membrane anchored ADAM9 overexpressed by both PCa cells and prostate CAFs, the secreted isoform of ADAM9 (sADAM9) was strongly detected in CAFs, but rarely in tumor cells, and that could be a serum marker for PCa patients. We demonstrated that functionally sADAM9 are characterized as chemoattractant for the directed movement of androgen-independent PCa cells through integrin downstream FAK/AKT pathway, supporting that elevated sADAM9 by prostate CAFs could be responsible for the promotion of CRPC metastasis. Moreover, by stimulating PCa cells with sADAM9, we found that ubinuclein-2 (UBN2) expression was increased. A positive correlation of ADAM9 and UBN2 expression was observed in androgen receptor-expressing PCa cell lines and further confirmed in clinical PCa specimens. Using a genetic modification approach, we identified UBN2 as a downstream target gene of ADAM9 that is critical for the survival of androgen-dependent PCa cells in response to androgen deprivation, through the induction and effect of the aldo-keto reductase family 1 member C3 (AKR1C3). Collectively, our results reveal a novel action of ADAM9 on the transition of androgen-dependent PCa cells into an androgen-independent manner through the UBN2/AKR1C3 axis; the aforementioned action could contribute to the clinically-observed acquired androgen-deprivation therapy resistance.

Alpha-1 blocker use increased risk of subsequent renal cell carcinoma: A nationwide population-based study in Taiwan.

Elevated Renal cell carcinoma (RCC) risk has been associated with the use of several antihypertensive medications but has not yet been elucidated in the populations prescribed alpha-1 blockers that are commonly used in the treatment of hypertension and lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS-BPH). The aim of the present study was to investigate the association between alpha-1 blocker use and the risk of developing RCC using a nationwide population-based database in Taiwan. Patients who were treated with alpha-1 blockers for at least 28 days were identified through the Taiwan National Health Insurance Research Database from 2000 to 2010. The unexposed participants were matched with the exposed cases according to age, sex, and index year at a ratio of 3:1. Cox proportional hazards regression, stratified by sex and comorbidities and adjusted for age, was performed to estimate hazard ratios (HRs) for the risk of subsequent RCC. Among 2,232,092 subjects, patients who received alpha-1 blocker treatment had a higher risk of RCC than the unexposed group. Taking into account hypertension and BPH, the adjusted HR was significantly higher in male alpha-1 blocker users who had no BPH and either the presence (HR: 1.63, 95% confidence interval [CI] = 1.22-2.18) or absence (HR: 2.31, 95% CI = 1.40-3.81) of hypertension than in men not receiving these drugs. Taken together, male alpha-1 blocker users who had no comorbidity of BPH exhibited an increased risk for developing RCC independent of hypertension. Further study is warranted to elucidate the underlying mechanisms of this association.

Synthesis and characterization of magnetic nanoparticles coated with polystyrene sulfonic acid for biomedical applications.

The development of novel magnetic nanoparticles (MNPs) with satisfactory biocompatibility for biomedical applications has been the subject of extensive exploration over the past two decades. In this work, we synthesized superparamagnetic iron oxide MNPs coated with polystyrene sulfonic acid (PSS-MNPs) and with a conventional co-precipitation method. The core size and hydrodynamic diameter of the PSS-MNPs were determined as 8-18 nm and 50-200 nm with a transmission electron microscopy and dynamic light scattering, respectively. The saturation magnetization of the particles was measured as 60 emu g-1 with a superconducting quantum-interference-device magnetometer. The PSS content in the PSS-MNPs was 17% of the entire PSS-MNPs according to thermogravimetric analysis. Fourier-transform infrared spectra were recorded to detect the presence of SO3 - groups, which confirmed a successful PSS coating. The structural properties of the PSS-MNPs, including the crystalline lattice, composition and phases, were characterized with an X-ray powder diffractometer and 3D nanometer-scale Raman microspectrometer. MTT assay and Prussian-blue staining showed that, although PSS-MNPs caused no cytotoxicity in both NIH-3T3 mouse fibroblasts and SK-HEP1 human liver-cancer cells up to 1000 µg mL-1, SK-HEP1 cells exhibited significantly greater uptake of PSS-MNPs than NIH-3T3 cells. The low cytotoxicity and high biocompatibility of PSS-MNPs in human cancer cells demonstrated in the present work might have prospective applications for drug delivery.