Platelet-derived extracellular vesicles are associated with kidney injury in patients with urosepsis.

BACKGROUND: There is increasing evidence that platelet-derived extracellular vesicles (PEVs) may be involved in the mechanisms of inflammatory storm and organ damage in sepsis. However, there are no available studies on PEVs and renal injury in patients with urosepsis. METHODS: We analyzed the concentration and ratio of PEVs in plasma by flow cytometry and measured plasma IL-1ß/IL-6/TNF-α/NGAL levels by ELISA. Correlation analysis was also used to examine the concentration of PEVs in relation to levels of inflammatory factors and indicators of kidney damage, as well as the severity of the disease. Finally, the receiver operating characteristic curves were produced for PEVs concentrations as a diagnosis of S-AKI/AKI. RESULTS: We found significantly higher levels of IL-1ß/IL-6/TNF-α/NGAL in patients with urogenital sepsis. Furthermore, the concentrations of PEVs in plasma were significantly elevated in patients with urosepsis, especially in patients with Gram-negative bacterial infections, which were significantly and positively correlated with IL-1ß/IL-6/TNF-α/NGAL levels. The area under the curve for PEVs diagnosing S-AKI and AKI was 0.746 [0.484, 1.000] and 0.943 [0.874, 1.000] respectively. CONCLUSION: Overall, the present study suggested that PEVs may mediate the release of inflammatory mediators in patients with urosepsis and participate in the mechanism of acute kidney injury, as well as having potential as diagnostic indicators of S-AKI and AKI and as early warning indicators of the severity of patients with urosepsis.

Association between grip strength and stress urinary incontinence of NHANES 2011-2014.

OBJECTIVES: To investigate the association between grip strength (GS) and relative grip strength (rGS) with the prevalence and severity risk of SUI. METHODS: Female patients were retrieved from the NHANES 2011-2014. GS was measured using a digital hand dynamometer, rGS was defined as grip strength divided by BMI. Samples were classified into four groups based on quartiles of GS and rGS distribution (Q1-Q4)。Logistic regression models were established to detect the relationship between GS or rGS and SUI. The potential bias of baseline variables between SUI and non-SUI groups was controlled by performing the propensity score matching (PSM). RESULTS: A total of 4263 samples were included, with 3085 (85%) people in non-SUI group and 1178 (27.6%) people in SUI group. GS and rGS levels of people without SUI were higher than that of SUI patients. Monthly SUI patients' GS and rGS levels were higher than weekly SUI patients' level. Logistic regression analysis showed that risks of prevalence and severity of SUI decreased with increasing levels of GS and rGS. rGS was found to have a stronger association with SUI than GS [prevalence: GS: Q4 vs. Q1: aOR = 0.633, 95%CI = 0.508-0.789, p < 0.001; rGS: Q4 vs. Q1: aOR = 0.365, 95%CI = 0.290-0.459, p < 0.001; severity: GS: Q4 vs. Q1: aOR = 0.727, 95%CI = 0.600-0.881, p = 0.001; rGS: Q4 vs. Q1: aOR = 0.371, 95%CI = 0.282-0.488, p < 0.001]. The results of PSM confirmed that GS and rGS were correlated with SUI. CONCLUSIONS: Lower levels of GS and rGS are associated with an increased prevalence and severity risk of SUI.

Fibrinogen Is Associated with Prognosis of Critically Ill Patients with Sepsis: A Study Based on Cox Regression and Propensity Score Matching.

Introduction: Sepsis is a common syndrome in critically ill patients. Fibrinogen was reported to be associated with the prognosis of sepsis patients. Materials and Methods: Data was acquired from Multiparameter Intelligent Monitoring in Intensive Care Database IV (MIMIC-IV) version 1.0. Cox proportional hazards regression was utilized to estimate the relationship between fibrinogen and inhospital mortality. The cumulative incidence of mortality by fibrinogen level was estimated through the Kaplan-Meier curve. Restricted cubic spline (RCS) was used to assess nonlinear relationship. Subgroup analysis was also conducted to evaluate the robustness of the association between fibrinogen and inhospital mortality. Propensity score matching (PSM) was applied to adjust for confounding factors. Results: A total of 3365 patients, including 2031 survivors and 1334 nonsurvivors, were enrolled in our study. The survivors had a significantly elevated levels of fibrinogen compared with the deceased. The elevated level of fibrinogen was significantly associated with a decrease in mortality in multivariate Cox regression before and after PSM (HR 0.66, P < 0.001 and HR 0.73, P < 0.001, respectively). RCS showed a nearly linear relationship. Subgroup analysis demonstrated the robustness of the association in most subpopulations. However, the association between decreased levels of fibrinogen and increased inhospital mortality was denied after PSM. Conclusion: The elevated level of fibrinogen hints at better overall survival in critically ill patients with sepsis. Decreased levels of fibrinogen may be of little value in identifying patients with a high risk of death.

Expression of FOXA1 Is Associated with the Tumor-Infiltrating M2 Macrophage, Cytotoxic T Lymphocyte, and Effect of Chemotherapy in Bladder Cancer.

PURPOSE: Cisplatin-containing combination chemotherapy has been the standard of care since the late 1980s, but the response rate is <50%. Studies have shown that the efficiency of chemotherapy differs among molecular subtypes of bladder cancer. In this study, we aimed to correlate FOXA1, a marker for differentiation of the basal and luminal subtypes, with tumor immune cell infiltration and the effect of chemotherapy in bladder cancer. MATERIALS AND METHODS: Eighty-three patients with bladder cancer treated with chemotherapy were reviewed. Clinicopathological variables for each case were recorded. FOXA1, M2 tumor-associated macrophage (TAM), dendritic cell (DC), and cytotoxic T lymphocyte (CTL) were examined by immunohistochemistry. The relationship between FOXA1, immune cell infiltration, and clinical response to chemotherapy was assessed. RESULTS: The overall objective response rate was 34%. The objective response rate for tumors with lower FOXA1 expression was 58% and for tumors with higher FOXA1 expression was 12%. Tumors with infiltrated M2 TAM proportion <3% had a higher objective response rate compared with infiltrated M2 TAM proportion >3% tumors (46% vs. 21%, p = 0.02). Tumors with infiltrated CTL proportion >5% had a higher objective response rate compared with infiltrated CTL proportion <5% tumors (50% vs. 17%, p = 0.002). DCs showed no significant differences. We found that the objective response rate for tumors with lower FOXA1 expression, proportion <3% M2 TAM infiltration, and proportion >5% CTL infiltration is 82%. Lower FOXA1 expression was associated with low M2 TAM infiltration and high CTL infiltration. CONCLUSIONS: Thus, we showed that in patients with bladder cancer who received chemotherapy, the higher clinical response rate is associated with low FOXA1 expression, low M2 TAM infiltration, and high CTL infiltration.

Circular RNA circPOLR2A promotes clear cell renal cell carcinoma progression by facilitating the UBE3C-induced ubiquitination of PEBP1 and, thereby, activating the ERK signaling pathway.

BACKGROUND: Increasing evidence has demonstrated that circular RNAs (circRNAs) are implicated in cancer progression. However, the aberrant expression and biological functions of circRNAs in clear cell renal cell carcinoma (cRCC) remain largely elusive. METHOD: Differentially expressed circRNAs in cRCC were filtered via bioinformatics analysis. Aberrant circPOLR2A expression was validated in cRCC tissues and cell lines via qRT-PCR. Sanger sequencing was used to identify the backsplicing site of circPOLR2A. In vitro and in vivo functional experiments were performed to evaluate the role of circPOLR2A in cRCC malignancy. RNA pull-down, mass spectrometry, RIP, FISH and immunofluorescence assays were used to identify and validate the circPOLR2A-interacting proteins. Ubiquitination modification and interaction between proteins were detected via Co-IP and western blotting. The m6A modification in circPOLR2A was validated by the meRIP assay. RESULTS: Bioinformatics analysis revealed that circPOLR2A was highly expressed in cRCC tissues and metastatic cRCC tissues. CircPOLR2A expression was associated with tumor size and TNM stage in cRCC patients. In vitro and in vivo functional assays revealed that circPOLR2A accelerated cRCC cell proliferation, migration, invasion and angiogenesis, while inhibiting apoptosis. Further mechanistic research suggested that circPOLR2A could interact with UBE3C and PEBP1 proteins, and that UBE3C could act as a specific ubiquitin E3 ligase for the PEBP1 protein. The UBE3C/circPOLR2A/PEBP1 protein-RNA ternary complex enhanced the UBE3C-mediated ubiquitination and degradation of the PEBP1 protein which could inactivate the ERK signaling pathway. Rescue experiments revealed that the PEBP1 protein was the functional downstream target of circPOLR2A. Furthermore, m6A modification in circPOLR2A was confirmed, and the m6A reader YTHDF2 could regulate circPOLR2A expression. CONCLUSION: Our study demonstrated that circPOLR2A modulated the UBE3C-mediated ubiquitination and degradation of the PEBP1 protein, and further activated the ERK pathway during cRCC progression and metastasis. The m6A reader, YTHDF2, regulated circPOLR2A expression in cRCC. Hence, circPOLR2A could be a potential target for the diagnosis and treatment of cRCC.

Fibrinogen and antithrombin III are associated with in-hospital mortality among critically ill patients with acute kidney injury.

OBJECTIVES: Coagulation factors participates in the inflammatory cascade, known to play a crucial role in the development of acute kidney injury (AKI). Thus, it's likely that some factors may be associated with AKI. Among them, low levels of fibrinogen and antithrombin III (ATIII) activity have been proved to increase mortality in patients with sepsis. Moreover, they are also reported to be associated with higher incidence of AKI. However, the association between coagulation parameters, especially fibrinogen and ATIII, and prognosis of AKI has not been examined. METHODS: Data were acquired from Multiparameter Intelligent Monitoring in Intensive Care Database IV (MIMIC-IV) version 1.0. Cox proportional hazards regression model was used to estimate the relationship between coagulation parameters and in-hospital mortality in critically ill patients with AKI. Subgroup analysis was also conducted to assess the robustness of the association. Restricted cubic spline (RCS) curve was utilized to examine the nonlinear relationships between fibrinogen or ATIII and in-hospital mortality. Kaplan-Meier method was used to estimate cumulative incidence of mortality by fibrinogen or ATIII levels. Receiver-operating characteristic (ROC) curve was plotted and area under curve was calculated to evaluate predictive ability of fibrinogen or ATIII. RESULTS: A total of 5914 eligible patients were enrolled in fibrinogen cohort study and 115 patients were eligible for ATIII cohort study. The baseline of low fibrinogen (<150 mg/dL) or ATIII (<80%) activity was associated with significantly higher in-hospital mortality (fibrinogen HR [95% CIs] 2.01 [1.79, 2.27]; ATIII 3.73 [1.11, 12.54]). The HR [95% CIs] of low fibrinogen remained significant 1.29 (1.13, 1.48) in multivariate analysis. The RCS curve showed nearly linear relationship. Subgroup analysis also proved the robustness of the association between fibrinogen and in-hospital mortality. Kaplan-Meier survival curve and ROC demonstrated the predictive capability of fibrinogen and ATIII. CONCLUSION: Low fibrinogen is an independent predictor of in-hospital mortality in critically ill patients with AKI. Low ATIII activity is also likely to impact the risk of in-hospital death.

Bortezomib alleviates antibody-mediated rejection in kidney transplantation by facilitating Atg5 expression.

Antibody-mediated rejection (AMR) is one of the most dominant mechanisms responsible for the loss of kidney grafts. Previous researches have shown that donor-specific antibodies (DSAs) are the major mediators of AMR. In order to prolong the survival time of grafts, it is vital to reduce the incidence of AMR and inhibit the generation of DSAs. We established an animal model of AMR by performing kidney transplantation in pre-sensitized rats. Then, we investigated the effect of bortezomib (BTZ) on AMR. We found that BTZ could reduce the serum level of DSAs and alleviate post-transplantation inflammation in peritubular capillaries (PTCs) and glomeruli, which was demonstrated by the reduction of C4d and IgG deposition in PTCs, and the reduced number of B cell and plasma cell in peripheral blood and the transplanted kidney (p < 0.05). Our results also suggested that BTZ increased the number of regulatory T cell (Treg) and significantly reduced the proportion of T helper (Th17) cell (p < 0.05). Besides, BTZ induced the significant upregulation of anti-inflammatory cytokines but downregulated pro-inflammatory cytokines (p < 0.05). After dealing with Atg5 siRNA-lentivirus, the effect of BTZ alleviating AMR was reversed and Th17/Treg proportions were also significantly modulated. Collectively, these findings show that BTZ slows down the process of AMR and Atg5 may be the key mechanism. Furthermore, Atg5 silencing results may be demonstrated that Atg5 alleviated AMR by modulating the ratio of Th17/Treg.

ciRS-7 is a prognostic biomarker and potential gene therapy target for renal cell carcinoma.

Circular RNAs are a new class of non-coding RNAs that have been shown to play critical roles in the development and progression of renal cell carcinoma (RCC). However, little is known about the functional mechanisms and therapeutic role of ciRS-7 in RCC. A series of in vitro and in vivo experiments were performed to investigate the functional mechanism and therapeutic role of ciRS-7, such as real-time quantitative PCR, CCK-8, wound healing, transwell, colony formation, Edu, tumor xenograft and lung metastasis in NSG mice. RNA pull-down, dual luciferase reporter, fluorescence in situ hybridization (FISH) and rescue assays were used to determine the relationship between ciRS-7, miR-139-3p and TAGLN. In addition, we constructed PBAE/si-ciRS-7 nanocomplexes with PBAE material to evaluate the therapeutic effect of the nanocomplexes on tumor in vivo. ciRS-7 was highly expressed in RCC tumor tissues and cell lines, and high ciRS-7 expression correlated with tumor size, high Fuhrman grade and poor survival. Depletion of ciRS-7 significantly inhibited RCC cell proliferation, invasion, tumor growth and metastasis in vivo, while overexpression of ciRS-7 had the opposite effect. Mechanistically, ciRS-7 acts as a "ceRNA" for miR-139-3p to prevent TAGLN degradation and promoting RCC progression and metastasis via the PI3K/AKT signaling pathway. In addition, miR-139-3p mimics or inhibitor could reverse the altered malignant tumor behavior caused by ciRS-7 overexpression or silencing. Furthermore, the PBAE/siciRS-7 nanocomplexes could significantly inhibit RCC tumor progression and metastasis in vivo. ciRS-7 acts as a tumor promoter by regulating the miR-139-3p/TAGLN axis and activating the PI3K/AKT signaling pathway to promote RCC progression and metastasis. Drug development of PBAE/si-ciRS-7 nanocomplexes targeting ciRS-7 may represent a promising gene therapeutic strategy for RCC.

Carbon monoxide enhances calcium transients and glucose-stimulated insulin secretion from pancreatic ß-cells by activating Phospholipase C signal pathway in diabetic mice.

In early stage of diabetes, insulin secretion from pancreatic ß-cells is increased to deal with the elevated blood glucose. Previous studies have reported that islet-produced carbon monoxide (CO) is associated with increased glucose-stimulated insulin secretion from ß-cells. However, this compensatory mechanism by which CO may act to enhance ß-cell function remain unclear. In this study, we revealed that CO promoted intracellular calcium ([Ca2+]i) elevation and glucose-stimulated insulin secretion (GSIS) from pancreatic ß-cells in leptin receptor deficient db/db mice but not in C57 mice. The stimulatory effects of CO on ß-cell function in db/db mice was blocked by inhibition of Phospholipase C (PLC) signaling pathway. We further demonstrated that CO triggered [Ca2+]i transients and enhanced GSIS in C57 islets when ß-cells overexpressed with PLCγ1 and PLCδ1, but not PLCß1. On the other hand, reducing PLCγ1 and PLCδ1 expressions in db/db islets dramatically attenuated the stimulatory effects of CO on ß-cell function, whereas interfering PLCß1 expression had no effects on CO-induced ß-cell function enhancement. Our findings showing that CO elevated [Ca2+]i and enhanced GSIS by activating PLC signaling through PLCγ1 and PLCδ1 isoforms in db/db pancreatic ß-cells may suggest an important mechanism by which CO promotes ß-cell function to prevent hyperglycemia. Our study may also provide new insights into the therapy for type II diabetes and offer a potential target for therapeutic applications of CO.

[Nur77 inhibits the proliferation of prostate cancer cells].

OBJECTIVE: To study the effects of Nur77 on prostate cancer (PCa) cell growth and its potential value in the treatment of PCa. METHODS: We detected the expression of the NUR77 protein in human PCa tissues and cells by Western blot and determined the effects of Nur77 on the proliferation and apoptosis of the PCa cells by flow cytometry. RESULTS: Nur77 and AR were expressed in the human PCa tissue and cells, and overexpressed NUR77 inhibited the proliferation and cell cycle progression of the PCa LNCaP cells. The small-molecule receptor agonists cytosporone B and DIMC of Nur7 significantly suppressed the growth and induced the apoptosis of the PCa LNCaP cells. CONCLUSIONS: Nur77 inhibits the proliferation and induces the apoptosis of PCa cells, and is expected to be a potential molecular target for the treatment of PCa.

Epigenetically modifying the Foxp3 locus for generation of stable antigen-specific Tregs as cellular therapeutics.

Foxp3+ regulatory T cells (Tregs) are potent immunoregulatory cells, prompting strong interests in manipulating them for therapeutic purposes. However, significant challenges remain, including their heterogeneity and functional instability. Here we focused on the inducible Tregs (iTregs) and studied whether the Foxp3 locus can be epigenetically edited ex vivo to produce stable therapeutic iTregs. Under iTreg-inducing condition where activated CD4+ T effector cells were converted to Foxp3+ Tregs, we tested approximately 30 compounds and identified 3 chromatin-modifying chemical compounds (3C) consisting of sodium butyrate (a broad histone deacetylase inhibitor), UNC0646 (a histone methyltransferase inhibitor), and vitamin C (a TET dioxygenase co-activator), that together produced complete demethylation at the conserved noncoding sequence 2 (CNS2) region of Foxp3 locus. We found that iTregs induced in the presence of 3C (3C-iTregs) are stable, even after exposure to inflammatory cytokines. They expressed high levels of Foxp3 and exhibited potent suppressive activities both in vitro and in vivo. We showed that in models of autoimmunity and transplant rejection, adoptive transfer of antigen-specific 3C-iTregs prevented the induction of experimental autoimmune encephalitis and enabled long-term skin allograft survival. Our data demonstrate that the Foxp3 locus can be epigenetically edited ex vivo to generate stable therapeutic iTregs.

The many shades of macrophages in regulating transplant outcome.

The shift of emphasis from short-term to long-term graft outcomes has led to renewed interests in how the innate immune cells regulate transplant survival, an area that is traditionally dominated by T cells in the adaptive system. This shift is driven largely by the limited efficacy of current immunosuppression protocols which primarily target T cells in preventing chronic graft loss, as well as by the rapid advance of basic sciences in the realm of innate immunity. In fact, the innate immune cells have emerged as key players in the allograft response in various models, contributing to both graft rejection and graft acceptance. Here, we focus on the macrophages, highlighting their diversity, plasticity and emerging features in transplant models, as well as recent developments in our studies of diverse subsets of macrophages. We also discuss challenges, unsolved questions, and emerging approaches in therapeutically modulating macrophages in further improvement of transplant outcomes.

Role of the NF-κB Family Member RelB in Regulation of Foxp3+ Regulatory T Cells In Vivo.

The NF-κB family member RelB is an important transcription factor that is capable of regulating diverse immune and inflammatory responses. However, its role in the regulation of Foxp3+ regulatory T cells (Tregs) in vivo is poorly defined. In this study, we demonstrated that germline deletion of Relb resulted in systemic autoimmunity, which is associated with significant accumulation of Foxp3+ Tregs in lymphoid and nonlymphoid organs. Foxp3+ Tregs from RelB-deficient mice were functional and capable of suppressing T effector cells in vitro and in vivo, but Foxp3- T effector cells from RelB-deficient mice showed features of hyperactivation and spontaneously produced high levels of IL-2. Surprisingly, mice with conditional deletion of Relb in T cells (Cd4CreRelbf/f mice) or specifically in Foxp3+ Tregs (Foxp3CreRelbf/f mice) did not show signs of autoimmunity and had similar frequencies of Foxp3+ Tregs in the periphery as wild-type C57BL/6 controls. Both strains of conditional knockout mice also had a normal conventional T cell compartment. However, reconstituting Rag-1-/-Relb-/- hosts with wild-type C57BL/6 bone marrow cells led to hyperactivation of T effector cells, as well as marked expansion of Foxp3+ T cells. These data suggest that the autoimmune phenotype in germline RelB-deficient mice is most likely caused by T cell-extrinsic mechanisms, and further studies are warranted to uncover such mechanisms.

Exploration of IMDC model in patients with metastatic renal cell carcinoma using targeted agents: a meta-analysis.

PURPOSE: To explore the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model application for predicting outcome of patients with metastatic renal cell carcinoma using targeted agents. MATERIALS AND METHODS: We performed a literature review of 989 articles. The selecting process used preferred reporting items for systematic reviews and meta-analyses (PRISMA). All included studies were assessed by Newcastle-Ottawa scale. Results of individual studies were pooled using Stata 14.0 software. RESULTS: A total of 17 articles were included. Most articles provided univariate and multivariate analysis of IMDC model prognosis. Combined HRs were 1.58 (95% CI 1.34-1.82) and 3.74 (95% CI 2.67-4.81) for univariate PFS of intermediate to favorable and poor to favorable respectively. In the category of multivariate PFS, combined HRs were 1.27 (95% CI 0.99-1.56) and 2.29 (95% CI 1.65-2.93) with intermediate to favorable and poor to favorable respectively. Regarding univariate OS, combined HRs were 1.93 (95% CI 1.62-2.24) and 6.25 (95% CI 4.18-8.31) with intermediate to favorable and poor to favorable respectively. With multivariate OS, combined HRs were 1.32 (95%CI 1.04-1.59) and 2.35 (95%CI 1.69-3.01) with intermediate to favorable and poor to favorable respectively. CONCLUSION: In summary, analysis of currently available clinical evidence indicated that IMDC model could be applied to classify patients with metastatic renal cell carcinoma using targeted agents. However, different types of targeted agents and various areas could affect the accuracy of the model. There was also a difference in predicting patients' PFS and OS.

[The transcription factor NF-kB1 regulates miR-195 expression in prostate cancer].

OBJECTIVE: To investigate the regulatory effect of the transcription factor NF-kB1 on the expression of miR-195 in prostate cancer (PCa). METHODS: We analyzed the possibility of NF-kB1 binding to the miR-195 promoter and the expression of NF-kB1 in PCa using the JASPAR and Oncomine databases, respectively, and determined the expressions of NF-kB1 and miR-195 in PCa cells by real-time quantitative PCR after inhibiting the former by interfering RNA targeting NF-kB1. We detected the activity of the luciferase reporter gene after constructing its gene plasmid in the miR-195 promoter region and having it co-transfected with the NF-kB1 plasmid. Then we analyzed the correlation between the expressions of miR-195 and NF-kB1 in the prostate tissue. RESULTS: NF-kB1 was overexpressed in PCa. After inhibition of the expression of NF-kB1, that of miR-195 was increased in PC-3 and DU-145 cell lines, with a negative correlation between the NF-kB1 and miR-195 expressions in the PCa tissue. The results of luciferase reporter gene assay showed direct binding of NF-kB1 to the miR-195 promoter zone. CONCLUSIONS: NF-kB1 regulates the expression of miR-195 in prostate cancer.

[Establishment of enzalutamide-resistant human prostate cancer cell lines and screening of lncRNA and mRNA expression profiles].

OBJECTIVE: To establish enzalutamide-resistant human prostate cancer cell lines and screen out the lncRNA and mRNA expression profiles associated with enzalutamide resistance. METHODS: Human prostate cancer cell lines LNCAP and C4-2B were cultured with 10 µmol/L enzalutamide for 6 months in vitro for the establishment of enzalutamide-resistant subclones LNCAP-ENZA and C4-2B-ENZA. The IC50 value and enzalutamide resistance index of each cell line were examined by MTT assay, the expressions of enzalutamide-related genes FL-AR, AR-V7 and HnRNPA1 were determined by Western blot, and the lncRNA and mRNA differential expressions of C4-2B and C4-2B-ENZA were detected by high-throughout lncRNA microarray. RESULTS: Compared with LNCAP and C4-2B, the IC50 values of enzalutamide-resistant subclones LNCAP-ENZA (60.83 µmol/L) and C4-2B-ENZA (88.32 µmol/L) were increased significantly (P < 0.05) and the enzalutamide-resistance indexes of the LNCAP-ENZA and C4-2B-ENZA cells were 4.94 and 4.67, respectively. The expressions of AR-V7 and HnRNPA1 were markedly up-regulated in the LNCAP-ENZA and C4-2B-ENZA cells as compared with those in the LNCAP and C4-2B cells, but that of FL-AR showed no significant change. A total of 1 440 lncRNAs and 1 236 mRNAs were identified as differentially expressed in the C4-2B-ENZA cells. CONCLUSIONS: Enzalutamide -resistant human prostate cancer cell subclones LNCAP-ENZA and C4-2B-ENZA were successfully established and enzalutamide resistance-associated lncRNA and mRNA were identified, which may provide some molecular evidence for the management of enzalutamide-resistant human prostate cancer.

hsa-miR-135a-1 inhibits prostate cancer cell growth and migration by targeting EGFR.

Prostate cancer is one of the leading causes of death in men worldwide. Differentially expressed microRNAs (miRNAs) are associated with metastatic prostate cancer. However, their potential roles for affecting prostate cancer initiation and progression remain largely unknown. Here, we examined the aberrant expression profiles of miRNAs in human metastatic prostate cancer tissues. We further validated our miRNA expression data using two large, independent clinical prostate cancer datasets from the Memorial Sloan Kettering Cancer Center (MSKCC) and The Cancer Genome Atlas (TCGA). Our data support a model in which hsa-miR-135-1 acts as a potential tumor suppressor in metastatic prostate cancer. First, its downregulation was positively correlated with late TNM stage, high Gleason score, and adverse prognosis. Second, cell growth, cell cycle progression, cell migration and invasion, and xenograft tumor formation were dramatically inhibited by miR-135a overexpression. Third, in the microarray gene expression data analysis using Gene Set Enrichment Analysis (GSEA), Database for Annotation, Visualization and Integrated Discovery (DAVID) analysis, Ingenuity Pathway Analysis (IPA), and Oncomine concept analysis, we showed that miR-135a targets multiple oncogenic pathways including epidermal growth factor receptor (EGFR), which we verified using functional experimental assays. These results help advance our understanding of the function of miRNAs in metastatic prostate cancer and provide a basis for further clinical investigation.

[Expression of SRD5A1 and its prognostic role in prostate cancer: Analysis based on the data-mining of ONCOMINE].

OBJECTIVE: To explore the expression of I-5α-reductase (SRD5A1)and its prognostic role in prostate cancer . METHODS: Data about SRD5A1 were retrieved from the ONCOMINE database and the role of SRD5A1 in prostate cancer was analyzed. RESULTS: Totally, 992 studies of different types relevant to the expression of SRD5A1 were identified in the ONCOMINE database. The SRD5A1 expression was statistically significant in 239 of the studies, overexpressed in 157 (11 in prostate cancer) and underexpressed in the other 82 (3 in prostate cancer). Eighteen of the studies, with 1 068 samples, addressed the expression of SRD5A1 in prostate cancer and normal tissues, which was significantly higher in the former than in the latter tissue (P<0.05). In 3 of the studies, the SRD5A1 expression was high in primary prostate cancer and increased with its metastasis (P<0.0 5). Two of the studies with prognostic data showed a higher rate of postoperative biochemical recurrence and a higher total mortality rate in the patients with a high than in those with a low expression of SRD5A1 (P<0.05). CONCLUSIONS: SRD5A1 is highly expressed in prostate cancer, especially in metastatic and castration-resistant prostate cancer and its expression is associated with the prognosis of prostate cancer, which may be an important target of medication for prostate cancer.

[Expression of long noncoding RNA LINC01358 in prostate cancer and its effect on the proliferation and migration of prostate cancer cells].

OBJECTIVE: To explore the expression of long noncoding RNA (lncRNA) LINC01358 in prostate cancer (PCa) and its effect on the proliferation and migration of PCa cells. METHODS: The lncRNA array was used to screen differentially expressed lncRNAs in PCa and the corresponding carcinoma-adjacent normal tissues from 3 patients. The expressions of LINC01358 in the primary PCa, metastatic PCa, and carcinoma-adjacent tissues were compared using the PCa dataset of the Memorial Sloan Kettering Cancer Center (MSKCC). The data obtained were validated by determining the expression of LINC01358 in the PCa and carcinoma-adjacent tissues of another 10 patients by quantitative real time PCR (qRT-PCR). The effects of lncRNA LINC01358 on the proliferation of DU145 cells and migration of PCa cells were detected by MTT and Transwell assay, respectively. RESULTS: Totally, 79 differentially expressed lncRNAs in the lncRNA array, 36 highly and the other 43 lowly expressed in the PCa tissue. LINC01358 was up-regulated in the cancerous tissue. According to the MSKCC data, the LINC01358 expression was markedly higher in metastatic PCa (5.81±0.19, n = 19) and primary PCa (5.47±0.04, n = 131) than in the PCa-adjacent tissue (5.15±0.07, n = 29) and significantly correlated with postoperative biochemical relapse of the malignancy (P<0.05). qRT-PCR indicated a remarkably higher expression of LINC01358 in the PCa than in the carcinoma-adjacent tissue (6.02±1.12 vs 3.21±0.21, P<0.05). Transfection of the DU145 cells with siRNA significantly decreased the level of LINC01358 and inhibited the proliferation and migration of the PCa cells. CONCLUSIONS: LINC01358 is highly expressed in the PCa tissue and knockdown of LINC01358 may inhibit the proliferation and migration of PCa cells. LncRNA LINC01358 may be involved in the development and progression of PCa and become an index for the early diagnosis as well as a new target for the gene therapy of the malignancy.