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Prognostic significance of GPC5 expression in patients with prostate cancer

The objective of this study was to evaluate the protein level of glypican-5 (GPC5) and its relationship with clinicopathologic significance in prostate cancer. The protein level of GPC5 in 160 prostate cancer tissues and 60 adjacent normal samples was examined by immunohistochemistry analysis, and the results were correlated with clinicopathologic parameters. The level of GPC5 in prostate cancer tissues was markedly lower than that in normal cases, especially in high-risk prostate cancer. Additionally, the low expression of GPC5 was closely associated with increased serum prostate-specific antigen (PSA), higher Gleason scores, advanced tumor stage (T3), positive lymph node metastasis, and biochemical recurrence. Moreover, GPC5 low expression was an independent prognostic factor for overall survival of patients with prostate cancer. GPC5 protein expression showed a close correlation with the tumorigenesis and tumor progression of prostate cancer, and that might be applied as a novel biomarker for the prediction of diagnosis and prognosis of prostate cancer.

Metformin Prevents Renal Stone Formation through an Antioxidant Mechanism In Vitro and In Vivo.

Oxidative stress is a causal factor and key promoter of urolithiasis associated with renal tubular epithelium cell injury. The present study was designed to investigate the preventive effects of metformin on renal tubular cell injury induced by oxalate and stone formation in a hyperoxaluric rat model. MTT assays were carried out to determine the protection of metformin from oxalate-induced cytotoxicity. The intracellular superoxide dismutase (SOD) activities and malondialdehyde (MDA) levels were measured in vitro. Male Sprague-Dawley rats were divided into control group, ethylene glycol (EG) treated group, and EG + metformin treated group. Oxidative stress and crystal formations were evaluated in renal tissues after 8-week treatment. Metformin significantly inhibited the decrease of the viability in MDCK cells and HK-2 cells induced by oxalate. Besides, metformin markedly prevented the increased concentration of MDA and the decreased tendency of SOD in oxalate-induced MDCK cells and HK-2 cells. In vivo, the increased MDA levels and the reduction of SOD activity were detected in the EG treated group compared with controls, while these parameters reversed in the EG + metformin treated group. Kidney crystal formation in the EG + metformin treated group was decreased significantly compared with the EG treated group. Metformin suppressed urinary crystal deposit formation through renal tubular cell protection and antioxidative effects.

GATA3-driven expression of miR-503 inhibits prostate cancer progression by repressing ZNF217 expression.

Although increasing evidence demonstrated that deregulation of mircoRNA-503 (miRNA-503) contributes to tumorigenesis, little is known about the biological role and intrinsic regulatory mechanisms of miR-503 in prostate cancer (PCa). In present study, we found that miR-503 was significantly downregulated in advanced PCa tissues and cell lines. Downregulation of miR-503 was strongly associated with aggressive clinical-pathological features and poor prognosis in PCa patients. Ectopic expression of miR-503 significantly inhibited tumor cells growth, cell migration and invasion in vitro and in vivo. Mechanistic studies revealed that ZNF217 was a direct target downstream target of miR-503. Knockdown of ZNF217 mimicked the tumor-suppressive effects of miR-503 overexpression on PCa invasion, whereas ZNF217 overexpression attenuated the tumor-suppressive function of miR-503. Subsequently, miR-503 further modulated the activation of ZNF217-downstream epithelial-mesenchymal transition (EMT) genes. Besides, we also found that GATA3 directly increased miR-503 expression and thus decreased ZNF217 expression, indicating the involvement of GATA3/miR-503/ZNF217 signaling in EMT process. Collectively, our results demonstrated that GATA3-driven expression of miR-503 inhibits PCa progression by repressing ZNF217 expression, and also implicated the potential application of miR-503 in PCa therapy.

The protective role of Nrf2-Gadd45b against antimony-induced oxidative stress and apoptosis in HEK293 cells.

Antimony (Sb) is one of the most prevalent heavy metals and frequently causes biological toxicity. However, the specific mechanisms by which Sb elicits its toxic effects remains to be fully elucidated. In this study, we found antimony trioxide (Sb2O3) caused a dose-dependent cytotoxicity against HEK293 cells, and Sb2O3-induced excessive reactive oxygen species (ROS) was closely correlated with increased cell apoptosis. Mechanistic investigation manifested that nuclear factor NF-E2-related factor 2 (Nrf2) expression and nuclear translocation were significantly induced under Sb2O3 treatment in HEK293 cells, and Nrf2 knockdown aggregated Sb2O3-induced cell apoptosis. Moreover, elevated Gadd45b expression actives the phosphorylation of MAPKs upon Sb2O3 exposure, whereas Gadd45b knockdown diminished Sb2O3-induced activation of MAPKs and promoted cell apoptosis. In the meantime, however, the antioxidant N-acetylcysteine (NAC) was found to ameliorate Nrf2 expression and nuclear translocation as well as Gadd45b expression and MAPKs activation by repressing Sb2O3-induced ROS production. More importantly, we found Gadd45b was transcriptionally enhanced by Nrf2 through binding to three canonical antioxidant response elements (AREs) within its promoter region. Either Sb2O3 or TBHQ (a selective Nrf2 activator) treatment, Gadd45b expression was significantly increased by luciferase assay. Nrf2 inhibition greatly diminished Gadd45b expression due to reduced binding of Nrf2 in Gadd45b promoter under Sb2O3 treatment. To summarize, this study demonstrated the Nrf2-Gadd45b signaling axis exhibited a protective role in Sb-induced cell apoptosis.

Elevated expression of ZNF217 promotes prostate cancer growth by restraining ferroportin-conducted iron egress

Although we and other studies indicated ZNF217 expression was increased in prostate cancer (PCa), the factors mediating its misregulated expression and their oncogenic activity remain largely unexplored. Recent evidence demonstrated that ferroportin (FPN) reduction lead to decreased iron export and increased intercellular iron that consequently aggravates the oncogenic effects of iron. In the present study, ZNF217 was identified as a transcriptional repressor that inhibits FPN expression. Increased of ZNF217 expression led to decreased FPN concentration, coupled with resultant intracellular iron retention, increased iron-related cellular activities and enhanced tumor cell growth. In contrast, decreased of ZNF217 expression restrained tumor cell growth by promoting FPN-driven iron egress. Mechanistic investigation manifested that ZNF217 facilitated the H3K27me3 levels of FPN promoter by interacting with EZH2. Besides, we also found that MAZ increased the transcription level of ZNF217, and subsequently inhibited the FPN expression and their iron–related activities. Strikingly, the expression of MAZ, EZH2 and ZNF217 were concurrently upregulated in PCa, leading to decreased expression of FPN, which induce disordered iron metabolism. Collectively, this study underscored that elevated expression of ZNF217 promotes prostate cancer growth by restraining FPN-conducted iron egress.

Pim-3 is a Critical Risk Factor in Development and Prognosis of Prostate Cancer.

Background Pim-3 kinase is a highly homologous serine/threonine kinase that is overexpressed in hematological malignancies and solid tumors. Few studies have been conducted to define the role of Pim-3 in solid tumors, especially in prostate cancer. The aim of this study was to define the role of Pim-3 in development and prognosis of prostate cancer. Material/Methods We collected specimens from 160 patients with prostate cancer, as well as 100 patients with benign prostatic hyperplasia. Realtime polymerase chain reaction was used for the assessment of Pim-3 expression at the RNA level and Western blot was used to quantify the Pim-3 protein synthesis in 3 different cell lines. Results We found that Pim-3 mRNA expression in prostate cancer tissue was significantly higher than that in benign prostatic hyperplasia tissue (p<0.05). Accordingly, the protein level expression of Pim-3 in prostate cancer cell lines was also significantly higher than that in control cells. In addition, the expression status of Pim-3 mRNA was significantly associated with pathological parameters such as pre-surgery prostate specific antigen, Gleason score, pathological stage, and lymphoid metastasis. High expression of Pim-3 also significantly decreased the survival rate of patients after surgery. Conclusions Pim-3 expression is an important risk factor for prostate cancer; we are the first team to report Pim-3 as a valuable biomarker in Chinese.

Low expression of TMEM67 is a critical predictor of poor prognosis in human urothelial carcinoma of the bladder

OBJECTIVES The aim of the study was to evaluate the expression of TMEM67 in urothelial carcinoma of the bladder (UCB) tissues and to determine the potential relevance between the expression of TMEM67 and prognosis of UCB. MATERIAL AND METHODS In this study, the expression of TMEM67 mRNA was performed by quantitative real-time PCR in 80 UCB and 54 noncancerous tissues. The expression of TMEM67 protein was identified by immunohistochemistry and western blotting. Chi-square test was conducted to verify the relevance between the expression of TMEM67 and clinical parameters. Kaplan-Meier survival analysis was demonstrated between high or low expression level of TMEM67 mRNA and recurrence-free survival probability. Cox regression analysis was conducted to evaluate the relevance between the expression of TMEM67 and the prognosis in UCB. RESULTS Low expression of TMEM67 mRNA and protein was detected in most of UCB tissues using quantitative real-time polymerase chain reaction and western blotting, compared with noncancerous tissues. Low expressions of TMEM67 were associated with TNM stage, grade, and lymph node metastasis (P<0.05). Kaplan-Meier analysis showed that the low expression of TMEM67 mRNA had significantly shorter recurrence-free survival probability (P = 0.018). Cox regression analysis confirmed that low expression of TMEM67 mRNA predicted poor prognosis of patients with UCB (HR = 2.950, P = 0.029, 95% CI: 1.116-7.796). CONCLUSIONS TMEM67 expression is low in UCB tissues, and the TMEM67 low expression predicted poor prognosis of patients with UCB.

Analysis of immune status after iodine-125 permanent brachytherapy in prostate cancer

Background Permanent prostate brachytherapy (PPB) is an effective treatment choice for low and intermediate risk prostate cancer (PCa). However, the impact of PPB on tumor immune status is still poorly understood. This study aimed to assess the immune status in PCa patients before and at different time points after PPB (1, 3, 6, and 12 months). Methods Blood was collected from 32 patients with low and intermediate risk PCa and 12 healthy volunteers. The frequency of immunocompetent cells was identified by flow cytometry. The concentration of immunoglobulins and complements was detected by ELISA. Results Various immunocompetent cells were dysregulated in PCa patients compared with healthy volunteers. Peripheral serum prostate-specific antigen (PSA) decreased rapidly at the first month after PPB treatment, and the peripheral serum PSA became very low at 6 months after PPB treatment. CD3+ T cells, CD4+ T cells, CD3-CD16+/56+ natural killer (NK) cells were increased significantly at certain time points after PPB. Although the percentage of the CD8+ T cells did not change markedly, the ratio of CD4/CD8 increased significantly at 3 months after PPB (P=0.0196). There was no influence of PPB on B cells number, but the concentration of immunoglobulins IgM, IgG, and IgA, and complements C3 and C4 in patients increased at some time points after PPB. Conclusion The immunocompetent cells are dysregulated in PCa patients. PPB treatment could effectively kill tumor cells and then stimulate cellular immunity and humoral immunity in PCa patients.

Multivariate Analyses of Urinary Calculi Composition: A 13-Year Single-Center Study.

The incidence and prevalence of urinary stone are increasing throughout the world. Compared to the past, recent demographics of patient with urolithiasis compositions are strikingly different. Furthermore, recent clinical studies implied that seasonal cyclicity might influence the distribution of stone composition.

Autophagic effects and mechanisms of silver nanoparticles in renal cells under low dose exposure

With the advancement of nanotechnology and unique properties, silver nanoparticles (AgNPs) have been generally used in our work and life. However, the concerns on nanosafety have not been thoroughly understood. Although mounting studies have documented AgNPs-mediated autophagy under toxic dose, very few studies have been made to reveal the mechanisms of AgNPs-induced autophagy at non-toxic concentrations. Here, we investigated AgNPs-mediated biological effects on autophagy in renal cells under sublethal exposure. Sublethal AgNPs resulted in increase of LC3II level and accumulation of autophagy related genes in HEK293T and A498 cells, which demonstrated AgNPs could activate autophagy at lower concentrations. Mechanistic investigation manifested that AMPK-mTOR signaling was enrolled in AgNPs-induced autophagy process rather than PI3K/AKT/mTOR signaling. In addition, P62 was elevated in AgNPs-treated cells in an mTOR-independent manner. We further uncovered that sublethal AgNPs exposure impaired the integrity and protease activities of lysosome. Together, our results revealed the mechanism by which AgNPs induced autophagy in renal cells under sublethal concentration.