Upregulation of long non-coding RNA MALAT1 correlates with tumor progression and poor prognosis in clear cell renal cell carcinoma.

Long noncoding RNAs (lncRNAs) have been investigated as a new class of regulators of cellular processes, such as cell growth, apoptosis, and carcinogenesis. LncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has recently been identified to be involved in tumorigenesis of several cancers such as lung cancer, pancreatic cancer, and cervical cancer. However, the role of lncRNA MALAT1 in clear cell renal cell carcinoma (ccRCC) remains unclear. Expression levels of lncRNA MALAT1 in ccRCC tissues and renal cancer cell lines were evaluated by quantitative real-time PCR (qRT-PCR), and its association with overall survival of patients was analyzed by statistical analysis. Small interfering RNA (siRNA) was used to suppress MALAT1 expression in renal cancer cells. In vitro assays were conducted to further explore its role in tumor progression. The expression level of MALAT1 was higher in ccRCC tissues and renal cancer cells compared to adjacent non-tumor tissues and normal human proximal tubule epithelial cells HK-2. The ccRCC patients with higher MALAT1 expression had an advanced clinical features and a shorter overall survival time than those with lower MALAT1 expression. And multivariate analysis showed that the status of MALAT1 expression was an independent predictor of overall survival in ccRCC. Additionally, our data indicated that knockdown expression of MALAT1 decreased renal cancer cell proliferation, migration, and invasion. Our data suggested that lncRNA MALAT1 was a novel molecule involved in ccRCC progression, which provided a potential prognostic biomarker and therapeutic target.

Up-regulation of flotillin-2 is associated with renal cell carcinoma progression.

Flotillin-2 (FLOT2) is a highly conserved protein isolated from caveolae/lipid raft domains that tether growth factor receptors linked to signal transduction pathway. FLOT2 has recently been identified to be involved in tumorigenesis of several cancers such as breast cancer, melanoma, and gastric cancer. However, the role of FLOT2 in renal cell carcinoma (RCC) remains unclear. The expression levels of FLOT2 in RCC patients and renal cancer cell lines were evaluated by quantitative real-time PCR (qRT-PCR) and Western blot. FLOT2 protein expression was also analyzed in archived paraffin-embedded RCC tissues using immunohistochemistry (IHC), and its association with overall survival of patients was analyzed by statistical analysis. Small-interfering RNA (siRNA) was used to suppress FLOT2 expression in RCC cell lines. In vitro assays were performed to further explore its role in tumor progression. The expression level of FLOT2 was higher in RCC tissues and cell lines than in corresponding adjacent normal tissues and normal human proximal tubule epithelial cell line HK-2. IHC analysis revealed high expression levels of FLOT2 in RCC specimens. The RCC patients with higher FLOT2 expression had an advanced clinical stage and poorer prognosis than those with lower FLOT2 expression. FLOT2 expression was an independent prognostic marker of overall RCC patient survival in a multivariate analysis. In vitro assays indicated that knockdown of FLOT2 reduced cell proliferation, migration, and invasion. Our data suggest that FLOT2 is a novel molecule involved in RCC progression, which provide a potential prognostic biomarker and therapeutic target.

Statin use and risk of kidney cancer: a meta-analysis of observational studies and randomized trials.

AIM: Clinical studies have shown that statin use may modify the risk of kidney cancer. However, these studies yielded different results. To quantify the association between statin use and risk of kidney cancer, we performed a detailed meta-analysis of published studies regarding this subject. METHODS: A literature search was carried out using MEDLINE, EMBASE and the Cochrane database between January 1966 and October 2012. Prior to performing a meta-analysis, the studies were evaluated for publication bias and heterogeneity. Fixed effect and random effect models were used to estimate summary relative risks (RR) and the corresponding 95% confidence intervals (CIs). Subgroup analyses and sensitivity analysis were also performed. RESULTS: A total of 12 (two randomized controlled trials, five cohort, and five case-control) studies contributed to the analysis. There was heterogeneity among the studies but no evidence of publication bias. Pooled results indicated a non-significant decrease of total kidney cancer risk among all statin users (RR = 0.92, 95% CI 0.71, 1.19). Long term statin use did not significantly affect the risk of total kidney cancer (RR = 1.01, 95% CI 0.83, 1.22). In our subgroup analyses, the results were not substantially affected by study design, confounder adjustment and gender. Furthermore, sensitivity analysis confirmed the stability of the results. CONCLUSION: The findings of this meta-analysis suggested that there was no association between statin use and risk of kidney cancer. More studies, especially randomized controlled trials and high quality cohort studies with larger sample size and well controlled confounding factors, are needed to confirm this association in the future.

Preventive effect of phosphodiesterase 5 inhibitor tadalafil on experimental post-pyelonephritic renal injury in rats.

BACKGROUND: To evaluate the effects of Tadalafil, a phosphodiesterase 5 enzyme inhibitor, on Escherichia coli-induced renal damage in an acute pyelonephritis (PN) rat model. METHODS: Experimental PN was induced in 32 Wistar rats, and four groups were formed: group 1 (no treatment), group 2 (antibiotic), group 3 (Tadalafil), and group 4 (antibiotic + Tadalafil). Antibiotic was given on days 3 to 8, and Tadalafil was administered between days 0 and 28 of bacterial inoculation. Half of the rats were killed on the ninth day (early period) and histopathological parameters, immunohistochemical renal fibrosis markers, and oxidant/antioxidant system activities were evaluated. The rest of the rats were killed at the sixth week of the study and evaluated for histopathological parameters and renal fibrosis markers. RESULTS: Inflammatory activity was significantly milder in rats treated with antibiotic + Tadalafil versus no treatment group both in the early and late periods. In the late period, interstitial fibrosis or tubular atrophy was lower in the antibiotic + Tadalafil group versus the no treatment and antibiotic groups, and in Tadalafil versus antibiotic group. Tadalafil administration significantly reduced renal malondialdehyde and nitric oxide levels and enhanced superoxide dismutase and catalase activities. In addition, circulating tumor necrosis factor α, interleukin 1ß was greatly reduced in Tadalafil group versus the no treatment group. CONCLUSIONS: We have provided the first evidence that phosphodiesterase 5 enzyme inhibitor Tadalafil ameliorates circulating inflammatory cytokines, reverses oxidant/antioxidant dysfunction and eventually possesses an overall protective effect on renal tissue from Escherichia coli-induced PN-related kidney injury. Phophodieterase 5 inhibitor might be a novel therapeutic target for PN.

Urinary neutrophil gelatinase-associated lipocalin, a biomarker for systemic inflammatory response syndrome in patients with nephrolithiasis.

BACKGROUND: The objective of this study was to determine the diagnostic value of neutrophil gelatinase-associated lipocalin (NGAL), C-reactive protein (CRP), and procalcitonin (PCT) in the prognosis of patients presenting with the systemic inflammatory response syndrome (SIRS) with nephrolithiasis. METHODS: Urine NGAL protein levels were measured by enzyme-linked immunosorbent assay in 87 patients presenting with nephrolithiasis who were diagnosed as SIRS. Additionally, 52 patients presenting with nephrolithiasis but without urinary tract infection and 30 healthy controls were also included in the study. Levels of serum CRP and PCT were also taken into consideration. RESULTS: Median urinary NGAL levels were significantly increased in the SIRS cohorts compared with nephrolithiasis without urinary tract infection patients (4.28 ng/mL versus 2.69 ng/mL, P < 0.001), and NGAL was markedly elevated even in the early stage of SIRS (3.23 ng/mL versus 2.69 ng/mL, P < 0.001). According to the receiver-operating characteristic analysis, NGAL demonstrated a high diagnostic value compared with either PCT or CRP. In the later stage of SIRS, NGAL remained a highly sensitive (76.8%) and specific (86.5%) diagnostic marker compared with either PCT or CRP. Moreover, the area under the curves of NGAL (0.822) were also superior to those seen in either PCT (0.657) or CRP (0.761). CONCLUSION: Urinary NGAL is a highly sensitive and specific predictor of SIRS for patients presenting with nephrolithiasis. Further study of NGAL as a reliable biomarker of SIRS is required.

VPA inhibits renal cancer cell migration by targeting HDAC2 and down-regulating HIF-1α.

Cell migration plays major roles in human renal cancer-related death, but the molecular mechanisms remain unclear. Valproic acid (VPA) is a broad-spectrum inhibitor of class I and II histone deacetylases and shows great anticancer activity in a variety of human cancers. In this study, we found that VPA significantly inhibited cell migration but not proliferation of human renal cancer ACHN cells. Mechanistic studies found that VPA significantly inhibited the expression of HIF-1α. Knockdown of HIF-1α could obviously inhibited cell migration, while over-expression of HIF-1α markedly rescued the inhibition of VPA on cell migration. Further studies found that knockdown of HDAC2 completely mimicked the effects of VPA on HIF-1α and cell migration, and over-expression of HIF-1α could also rescue the effects of HDAC2 knockdown on cell migration. Collectively, these results indicated that the potential of specific inhibition of HDAC2 by small molecular chemicals may lead to future therapeutic agents in human renal cancer treatment.

Statin use and risk of bladder cancer: a meta-analysis.

PURPOSE: Emerging evidence suggests that statins may decrease the risk of cancers. However, available evidence on bladder cancer is conflicting. To quantify the association between statin use and risk of bladder cancer, we performed a detailed meta-analysis of published studies regarding this subject. METHODS: A literature search was carried out using MEDLINE, EMBASE, and OVID databases between January 1966 and October 2012. Before meta-analysis, between-study heterogeneity and publication bias were assessed using adequate statistical tests. Fixed- and random-effect models were used to estimate summary relative risks (RR) and the corresponding 95 % confidence intervals (CIs). Potential sources of heterogeneity were detected by meta-regression. Subgroup analyses, sensitivity analysis, and cumulative meta-analysis were also performed. RESULTS: A total of 13 (three RCTs, five cohort, and five case-control) studies contributed to the analysis. There was heterogeneity among the studies, but no publication bias. Pooled results indicated a nonsignificant increase in total bladder cancer risk among all statin users [RR = 1.07, 95 % CI (0.95, 1.21)]. Long-term statin use did not significantly affect the risk of total bladder cancer [RR = 1.21, 95 % CI (0.92, 1.59)]. In our subgroup analyses, the results were not substantially affected by study design, region, and confounder adjustment. Furthermore, sensitivity analysis confirmed the stability of the results. CONCLUSIONS: The findings of this meta-analysis suggested that there was no association between statin use and risk of bladder cancer. More studies, especially RCTs, are needed to confirm this association.

A comparative study of thulium laser resection of the prostate and bipolar transurethral plasmakinetic prostatectomy for treating benign prostatic hyperplasia.

UNLABELLED: WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Thulium laser is a new generation of surgical laser. It is a minimally invasive technology with several advantages, including rapid vaporization and minimal tissue damage and bleeding. However, details regarding the safety and efficacy of thulium laser in treating BPH remains unknown. We performed a comparative study in 100 patients with BPH of the safety and efficacy of thulium laser resection of the prostate (TMLRP, n = 50) and bipolar transurethral plasmakinetic prostatectomy (TUPKP, n = 50). We found that the efficacy and indications were the same in TMLRP and TUPKP. In TUPKP, the morbidity of urethrostenosis was low, and was nearly bloodless in surgery and had higher safety. Nevertheless, TUPKP is more suitable for patients with larger prostate volume. OBJECTIVE: To compare the safety and short-term efficacy of thulium laser resection of the prostate (TMLRP) and bipolar transurethral plasmakinetic prostatectomy (TUPKP) for the treatment of patients with benign prostatic hyperplasia (BPH). METHODS: A total of 100 patients diagnosed with BPH were randomly divided into two groups, treated with either TMLRP (50, group 1) or TUPKP (50, group 2). There was no significant difference in preoperative variables such as age, prostate volume, prostate-specific antigen (PSA) level, International Prostate Symptom Score (IPSS), maximum urinary flow rate (Qmax ) and postvoid residual urine volume (PVR) between the two groups. The perioperative parameters and therapeutic effects were recorded and compared between the two groups. RESULTS: There were significant differences in the following parameters between the two groups (TMLRP vs TUPKP [mean ± SD]): operation duration, 61.2 ± 24.2 vs 30.14 ± 15.9 min; catheterization time, 1.8 ± 0.4 vs 3.2 ± 0.6 d; postoperative hospital stay, 3.3 ± 0.8 vs 4.1 ± 1.3 d. The volume of blood loss and postoperative bladder irrigation were significantly lower in TMLRP group than in the TUPKP group. At 1 month after the operation, there were four cases of urethral stricture in the TUPKP group. At 3 months after the operation, IPSS, quality of life (QoL), Qmax and PVR were significantly improved, with no significant difference between the two groups. CONCLUSIONS: TMLRP is superior to TUPKP in terms of safety, blood loss, recovery time and complication rate, and is as efficacious as TUPKP for treating BPH. Operation duration was significantly longer in the TMLRP group than in the TUPKP group.

Epigallocatechin gallate attenuates interstitial cystitis in human bladder urothelium cells by modulating purinergic receptors.

BACKGROUND: Epigallocatechin gallate (EGCG) has exhibited antitumor properties against bladder cancer. However, its effects in interstitial cystitis (IC) have not been investigated. METHODS: Here, we performed repeated cystoscopy and re-biopsy of bladder mucosa before and after intravesical irrigation of EGCG in eight patients diagnosed with IC based on clinical and histopathologic assessments. Six normal bladder tissue samples were obtained from age-, race-, and sex-matched asymptomatic control subjects. IC symptom index was used to compare the therapeutic effect in IC patients. Patient-derived bladder epithelial cells were cultured and cell stretch experiments and ATP assays were performed. The expression of purinergic receptors X1, X2, and X3, and Y1, Y2, and Y11, in biopsied samples was detected by Western blotting and real-time polymerase chain reaction, respectively. Moreover, the expression of inducible NO synthase, phosphorylated Akt, and phosphorylated NF-κB was also assessed. RESULTS: All EGCG-treated patients demonstrated different extents of remission of symptoms. We found a significant upregulation in P2X1, P2X2, and P2X3 receptor proteins and P2Y1, P2Y2, and P2Y11 receptor transcripts in IC patients. However, EGCG therapy attenuated the expression of all purinergic receptors. In addition, EGCG demonstrated prominent antioxidative and antiinflammatory effects via inhibition of the upregulation of iNOS and phosphorylated NF-κB. Furthermore, the stretch-activated release of ATP in cultured bladder urothelial cells was greater in cells derived from IC patients, compared with those from the control patients, but EGCG, at all concentrations tested, effectively abolished the increase in ATP release from stretched IC patient-derived cells. CONCLUSIONS: Our study suggests that inhibition of the expression of purinergic receptors and ATP release in urothelial cells by EGCG supports further development of EGCG as a novel therapeutic option for IC.

Novel evidence demonstrates that epithelial-mesenchymal transition contributes to nephrolithiasis-induced renal fibrosis.

PURPOSE: To investigate fibrotic lesions in renal tissues obtained from patients with large calculi, and to selectively evaluate the expression and clinical significance of Twist and E-cadherin in nephrolithiasis patients. METHODS: We recruited 50 patients with kidney stone and 32 matched healthy controls. We determined plasma creatinine (Cr) and corrected Cr clearance (CCr). For the 50 patients, we detected daily urine protein excretion. At the end of percutaneous nephroscopic lithotomy, we performed puncture biopsy to acquire kidney tissue. We obtained normal control kidney tissues from non-nephrolithiasis patients who received a surgical biopsy during open surgery. We determined the expression of Twist and E-cadherin by immunohistochemical staining and scored it with clinical parameters. In addition, we analyzed the degree of expression of Twist and its correlation with long-term renal survival. RESULTS: Overall, the renal function of patients significantly decreased, as indicated by Cr and reduced CCr compared with healthy controls. Activated Twist was strongly expressed in tubular epithelial cells from kidneys of nephrolithiasis patients, whereas we found little positive staining of Twist in normal kidneys. Meanwhile, the expression of E-cadherin was significantly suppressed in kidneys of nephrolithiasis patients. Twist expression was inversely correlated with E-cadherin expression; using multivariate analysis, data showed that the factors influencing renal survival in patients were CCr (relative ratio, 4.39; 95% confidence interval, 1.34-14.38; P = 0.013) and the extent of Twist expression (relative ratio, 3.45; 95% confidence interval, 1.10-10.68; P = 0.033). CONCLUSIONS: Our data suggest that the possible novel EMT marker molecule Twist and Twist staining might be a valuable index predicting renal fibrosis progression in human nephrolithiasis.

Microarray profiling of human renal cell carcinoma: identification for potential biomarkers and critical pathways.

AIMS: The aim of this study was to screen several novel genes associated with renal cell carcinoma (RCC), and analyze the gene functions and signal pathways which were critical to RCCs with DNA microarray. METHODS: The gene expression profile of GSE781 was downloaded from Gene Expression Omnibus database, including 9 RCC samples and 9 healthy controls. Compared with the control samples, differentially expressed genes (DEGs) of RCC was identified the by packages in R. The selected DEGs were further analyzed using bioinformatics methods. Gene ontology (GO) enrichment analysis was performed using Gene Set Analysis Toolkit and protein-protein interaction (PPI) network was constructed with prePPI. Then, pathway enrichment analysis to PPI network was performed using WebGestalt software. RESULTS: A total of 429 DEGs were down-regulated and 418 DEGs were up-regulated in RCC samples compared to healthy controls. A total of 11 remarkable enhanced functions and 13 suppressed functions were identified. PPI nodes of high degrees, such as JAK2, IL8, BMPR2, FN1 and NCR1, were obtained. The DEGs were classified and significantly enriched in cytokine and cytokine receptor pathway. CONCLUSION: The hub genes we find from RCC samples are not only bio-markers, but also may provide the groundwork for a combination therapy approach for RCCs.

Sustained complete response to first-line immunochemotherapy for highly aggressive TP53/MDM2-mutated upper tract urothelial carcinoma with ERBB2 mutations, luminal immune-infiltrated contexture, and non-mesenchymal state: a case report and literature review.

Background: Upper tract urothelial carcinoma (UTUC) is a rare malignancy. The management of metastatic or unresectable UTUC is mainly based on evidence extrapolated from histologically homologous bladder cancer, including platinum-based chemotherapy and immune checkpoint inhibitor alone, whereas UTUC exhibits more invasiveness, worse prognosis, and comparatively inferior response to treatments. First-line immunochemotherapy regimens have been attempted in clinical trials for unselected naïve-treated cases, but their efficacies relative to standard chemo- or immuno-monotherapy still remain controversial. Here, we present a case of highly aggressive UTUC for whom comprehensive genetic and phenotypic signatures predicted sustained complete response to first-line immunochemotherapy. Case presentation: A 50-year-old man received retroperitoneoscopic nephroureterectomy and regional lymphadenectomy for high-risk locally advanced UTUC. Postoperatively, he developed rapid progression of residual unresectable metastatic lymph nodes. Pathologic analysis and next-generation sequencing classified the tumor as highly aggressive TP53/MDM2-mutated subtype with features more than expression of programmed death ligand-1, including ERBB2 mutations, luminal immune-infiltrated contexture, and non-mesenchymal state. Immunochemotherapy combining gemcitabine, carboplatin, and off-label programmed death-1 inhibitor sintilimab was initiated, and sintilimab monotherapy was maintained up to 1 year. Retroperitoneal lymphatic metastases gradually regressed to complete response. Blood-based analyses were performed longitudinally for serum tumor markers, inflammatory parameters, peripheral immune cells, and circulating tumor DNA (ctDNA) profiling. The ctDNA kinetics of tumor mutation burden and mean variant allele frequency accurately predicted postoperative progression and sustained response to the following immunochemotherapy, which were mirrored by dynamic changes in abundances of ctDNA mutations from UTUC-typical variant genes. The patient remained free of recurrence or metastasis as of this publishing, over 2 years after the initial surgical treatment. Conclusion: Immunochemotherapy may be a promising first-line option for advanced or metastatic UTUC selected with specific genomic or phenotypic signatures, and blood-based analyses incorporating ctDNA profiling provide precise longitudinal monitoring.

piRNA-1742 promotes renal cell carcinoma malignancy by regulating USP8 stability through binding to hnRNPU and thereby inhibiting MUC12 ubiquitination.

Accumulating studies have confirmed that PIWI-interacting RNAs (piRNAs) are considered epigenetic effectors in cancer. We performed piRNA microarray expression analysis on renal cell carcinoma (RCC) tumor tissues and paired normal tissues and performed a series of in vivo and in vitro experiments to explore piRNAs associated with RCC progression and investigate their functional mechanisms. We found that piR-1742 was highly expressed in RCC tumors and that patients with high piR-1742 expression had a poor prognosis. Inhibition of piR-1742 significantly reduced tumor growth in RCC xenograft and organoid models. Mechanistically, piRNA-1742 regulates the stability of USP8 mRNA by binding directly to hnRNPU, which acts as a deubiquitinating enzyme that inhibits the ubiquitination of MUC12 and promotes the development of malignant RCC. Subsequently, nanotherapeutic systems loaded with piRNA-1742 inhibitors were found to effectively inhibit the metastasis and growth of RCC in vivo. Therefore, this study highlights the functional importance of piRNA-related ubiquitination in RCC and demonstrates the development of a related nanotherapeutic system, possibly contributing to the development of therapeutic approaches for RCC.

High level of circulating endothelial progenitor cells positively correlates with serum vascular endothelial growth factor in patients with renal cell carcinoma.

PURPOSE: Although accumulated evidence indicates that circulating endothelial progenitor cells contribute to tumor neovascularization, to our knowledge the level of these cells and its correlation with serum vascular endothelial growth factor in patients with renal cell carcinoma have not been studied. We measured this level and investigated its clinical significance in patients with renal cell carcinoma. MATERIALS AND METHODS: The level of circulating endothelial progenitor cells (percent of total peripheral blood mononuclear cells) was quantified by assaying the CD45(-)CD34(+)vascular endothelial growth factor receptor 2(+) cell phenotype in 53 patients with renal cell carcinoma, 33 with benign renal tumors and 40 healthy controls. Serum vascular endothelial growth factor was quantified. RESULTS: The mean circulating endothelial progenitor cell level in patients with renal cell carcinoma was 0.281%, significantly higher than in patients with benign renal tumors and healthy controls (0.073% and 0.076%, respectively, each p <0.001). Patients with stage III-IV renal cell carcinoma had a statistically higher level of these cells than those with stage I-II (0.339% vs 0.243%, p <0.001). The mean level in patients with renal cell carcinoma greater than 7 cm was 0.331%, significantly higher than in those with tumors 4 or less and 4 to 7 cm (0.225% and 0.231%, respectively, each p <0.001). Mean serum vascular endothelial growth factor in patients with renal cell carcinoma was higher than in patients with benign renal tumors and healthy controls (315.5 vs 34.6 and 26.9 pg/ml, respectively, each p <0.001). The preoperative circulating endothelial progenitor cell level positively correlated with serum vascular endothelial growth factor in patients with renal cell carcinoma (r = 0.710, p <0.001). Levels of these cells and of vascular endothelial growth factor significantly decreased postoperatively compared to preoperatively (0.081% vs 0.297% and 31.69 vs 310.70 pg/ml, respectively, each p <0.001). CONCLUSIONS: A high circulating endothelial progenitor cell level was found in patients with renal cell carcinoma, which positively correlated with serum vascular endothelial growth factor. Results support the potential use of circulating endothelial progenitor cells as a novel biomarker for renal cell carcinoma.

Novel insights into the roles and therapeutic implications of MUC1 oncoprotein via regulating proteins and non-coding RNAs in cancer.

Mucin 1 (MUC1) is a heterodimeric transmembrane glycoprotein that protects epithelial cells in mammals. The transmembrane C-terminal subunit (MUC1-C) plays a crucial role in oncogenesis. As an oncoprotein, MUC1-C regulates a number of proteins that are associated with tumorigenesis by interacting with oncoproteins, transcription factors, coactivators, etc., inducing proliferation, epithelial-mesenchymal transition (EMT), invasion, stemness, immune evasion, and drug resistance. Moreover, MUC1-C modulates the expression of non-coding RNAs (ncRNAs), which further regulate carcinogenesis by directly binding to specific proteins. ncRNAs can also affect MUC1 protein expression by targeting the MUC1 mRNA 3' untranslated region (UTR). A series of ncRNAs can modulate cancer development by regulating MUC1-C. This review focuses on the interaction of MUC1-C with proteins and ncRNAs in cancer progression. We also summarize the recent advances in immunotherapy with a focus on therapeutic approaches based on MUC1-C and nanocarrier complexes for cancer treatment.

Transfection with Plasmid-Encoding lncRNA-SLERCC nanoparticle-mediated delivery suppressed tumor progression in renal cell carcinoma.

BACKGROUND: The accumulating evidence confirms that long non-coding RNAs (lncRNAs) play a critical regulatory role in the progression of renal cell carcinoma (RCC). But, the application of lncRNAs in gene therapy remains scarce. Here, we investigated the efficacy of a delivery system by introducing the plasmid-encoding tumor suppressor lncRNA-SLERCC (SLERCC) in RCC cells. METHODS: We performed lncRNAs expression profiling in paired cancer and normal tissues through microarray and validated in our clinical data and TCGA dataset. The Plasmid-SLERCC@PDA@MUC12 nanoparticles (PSPM-NPs) were tested in vivo and in vitro, including cellular uptake, entry, CCK-8 assay, tumor growth inhibition, histological assessment, and safety evaluations. Furthermore, experiments with nude mice xenografts model were performed to evaluate the therapeutic effect of PSPM-NPs nanotherapeutic system specific to the SLERCC. RESULTS: We found that the expression of SLERCC was downregulated in RCC tissues, and exogenous upregulation of SLERCC could suppress metastasis of RCC cells. Furthermore, high expression DNMT3A was recruited at the SLERCC promoter, which induced aberrant hypermethylation, eventually leading to downregulation of SLERCC expression in RCC. Mechanistically, SLERCC could directly bind to UPF1 and exert tumor-suppressive effects through the Wnt/ß-catenin signaling pathway, thereby inhibiting progression and metastasis in RCC. Subsequently, the PSPM-NPs nanotherapeutic system can effectively inhibit the growth of RCC metastases in vivo. CONCLUSIONS: Our findings suggested that SLERCC is a promising therapeutic target and that plasmid-encapsulated nanomaterials targeting transmembrane metastasis markers may open a new avenue for the treatment in RCC.

A Cuproptosis-Related Gene Model For Predicting the Prognosis of Clear Cell Renal Cell Carcinoma.

Despite advances in its treatment, patients diagnosed with clear cell renal cell carcinoma (ccRCC) have a poor prognosis. The mechanism of cuproptosis has been found to differ from other mechanisms that regulate cell death, including apoptosis, iron poisoning, pyrophosphate poisoning, and necrosis. Cuproptosis is an essential component in the regulation of a wide variety of biological processes, such as cell wall remodeling and oxidative stress responses. However, cuproptosis-related genes' expression in ccRCC patients and their association with the patient's prognosis remain ambiguous. Evaluation of The Cancer Genome Atlas (TCGA) identified 11 genes associated with cuproptosis that were differently expressed in ccRCC and nearby nontumor tissue. To construct a multigene prognostic model, the prognostic value of 11 genes was assessed and quantified. A signature was constructed by least absolute shrinkage and selection operator (LASSO) Cox regression analysis, and this signature was used to separate ccRCC patients into different risk clusters, with low-risk patients having a much better prognosis. This five-gene signature, when combined with patients' clinical characteristics, might serve as one independent predictor of overall survival (OS) in ccRCC patients. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis demonstrated that cuproptosis-related genes were enriched in patients with ccRCC. Then, quantitative real-time PCR (qPCR) was employed to verify these genes' expression. Generally, research has indicated that cuproptosis-related genes are important in tumor immunity and can predict OS of ccRCC patients.

Combination of preoperative plasma fibrinogen and neutrophil-to-lymphocyte ratio to predict the prognosis for patients undergoing laparoscopic nephrectomy for renal cell carcinoma.

This study was conducted to investigate the prognostic significance of a combination of fibrinogen and neutrophil-to-lymphocyte ratio (NLR) named the F-NLR score as a novel indicator and further create nomograms for predicting the prognosis of patients with renal cell carcinoma (RCC) treated with laparoscopic nephrectomy. A total of 425 patients with RCC who underwent laparoscopic nephrectomy were included in this study. Then, we divided the patients based on the cut-off values of their F-NLR score into three categories: F-NLR 2 (both high fibrinogen and NLR), F-NLR 0 (both low fibrinogen and NLR), and F-NLR 1 (remaining patients). Cox regression analysis was performed to investigate the predictive performance of the F-NLR score on overall survival (OS) and cancer-specific survival (CSS). Predictive nomograms of F-NLR were established and internally validated. Time-dependent receiver operating characteristic (ROC) curve analysis was performed to assess the predictive accuracy of the nomogram, NLR, and fibrinogen as prognostic markers. The F-NLR 0, 1, and 2 groups included 226 (53.2%), 147 (34.6%), and 52 (12.2%) patients, respectively. Cox regression analysis showed that a high F-NLR score was significantly associated with poor prognosis and acted as an independent prognostic factor for OS and CSS (all P < 0.05). Predictive nomograms with F-NLR for OS (C-index: 0.773) and CSS (C-index: 0.838) were well developed. Time-dependent ROC results showed that nomograms containing F-NLR had better predictive performance than NLR and fibrinogen. F-NLR score was a novel effective prognostic biomarker for patients with RCC undergoing laparoscopic nephrectomy.

Protective effects of SP600125 on renal ischemia-reperfusion injury in rats.

BACKGROUND: Ischemia/reperfusion injury (IRI) has a negative effect on renal allograft survival. Using a rat model of kidney IRI in this study, we investigated the overall effect of selective c-Jun N-terminal kinase (JNK) inhibitor SP600125 on renal IRI events. METHODS: All 45 Fisher rats were anesthetized and renal IRI model was established by 45 min clamp of bilateral renal pedicles and 24 h reperfusion. Vehicle solution or SP600125 solution was intraperitoneally injected 45 min before ischemia, respectively. Analysis of renal histology, function, reactive oxygen species (ROS) expression, JNK phosphorylation status, as well as intra-renal pro-inflammatory cytokines expression was evaluated in this study. RESULTS: After IRI, the levels of blood urea nitrogen, creatinine, tissue malondialdehyde, TNF-α, IL-1ß, IL-6 were all elevated significantly, while superoxide dismutase, catalase activity were decreased. Histologic findings showed severe devastating lesions and increased rodent cell apoptosis; SP600125 effectively improved morphologic features, reversed above-mentioned parameters, and significantly attenuated c-Jun phosphorylation, as well as intra-renal pro-inflammatory cytokines expression compared with vehicle-treated group. CONCLUSION: These data demonstrate that inhibition of c-Jun with SP600125 is capable of attenuating renal IRI, which might be a novel therapy target.

[Laparoendoscopic single-site retroperitoneal adrenalectomy:a report of 7 cases].

OBJECTIVE: To summarize our preliminary clinical experiences of laparoendoscopic single-site (LESS) retroperitoneal adrenalectomy. METHODS: Since October 2009 to January 2011, the investigators have performed LESS retroperitoneal adrenalectomy for 7 patients with adrenal tumors. A waist axillary midline incision of around 2 - 3 cm was made and a single incision for inserting a homemade port. Cambridge endo flexible laparoscopic instrument and other common laparoscopic accessories were used during the surgical procedures. RESULTS: LESS retroperitoneal adrenalectomies were technically successful in 6 cases with no extra skin incisions, no conversion into an open procedure or standard laparoscopy. Conversion to standard laparoscopy (3 ports) was inevitable in one case. The reason for conversion was due to tumor size (6 cm). No perioperative complication occurred. The mean operative duration was 139 min (95 - 200 min), the mean volume of blood loss 96 ml (30 - 350 ml) and the mean hospital stay 5 d (3 - 8 d). CONCLUSION: LESS retroperitoneal adrenalectomy is technically feasible and safe for the treatment of small adrenal tumors.