Prognosis Of ccRCC Patients Research Articles

SETD2 mutation in renal clear cell carcinoma suppress autophagy via regulation of ATG12

Inactivating mutations in the SETD2 gene, encoding for a nonredundant histone H3 methyltransferase and regulator of transcription, is a frequent molecular feature in clear cell renal cell carcinomas (ccRCC). SETD2 deficiency is associated with recurrence of ccRCC and bears low prognostic values. Targeting autophagy, a conserved catabolic process with critical functions in maintenance of cellular homeostasis and cell conservation under stress condition, is emerging as a potential therapeutic strategy to combat ccRCC. Epigenetics-based pathways are now appreciated as key components in the regulation of autophagy. However, whether loss of function in the SETD2 histone modifying enzyme occurring in ccRCC cells may impact on their ability to undergo autophagy remained to be explored. Here, we report that SETD2 deficiency in RCC cells is associated with the aberrant accumulation of both free ATG12 and of an additional ATG12-containing complex, distinct from the ATG5–ATG12 complex. Rescue of SETD2 functions in the SETD2 deficiency in RCC cells, or reduction of SETD2 expression level in RCC cells wild type for this enzyme, demonstrates that SETD2 deficiency in RCC is directly involved in the acquisition of these alterations in the autophagic process. Furthermore, we revealed that deficiency in SETD2, known regulator of alternative splicing, is associated with increased expression of a short ATG12 spliced isoform at the depend of the canonical long ATG12 isoform in RCC cells. The defect in the ATG12-dependent conjugation system was found to be associated with a decrease autophagic flux, in accord with the role for this ubiquitin-like protein conjugation system in autophagosome formation and expansion. Finally, we report that SETD2 and ATG12 gene expression levels are associated with favorable respective unfavorable prognosis in ccRCC patients. Collectively, our findings bring further argument for considering the SETD2 gene status of ccRCC tumors, when therapeutic interventions, such as targeting the autophagic process, are considered to combat these kidney cancers.

Circular RNA hsa_circ_001895 serves as a sponge of microRNA-296-5p to promote clear cell renalcell carcinoma progression by regulating SOX12.

There is an urgent need to find novel potential therapeutic targets for the diagnosis and treatment of clear cell renal cell carcinoma (ccRCC) due to its highly invasive ability as a common urological malignant tumor. Circular RNAs (circRNAs) have been indicated as potentially critical mediators in various types of tumor progression. We first used qRT‐PCR analysis to find dysregulated circRNAs in ccRCC. A novel circRNA, hsa_circ_001895, was upregulated in ccRCC specimens and associated with metastatic properties of ccRCC. However, the tumorigenic mechanism of hsa_circ_001895 on ccRCC is yet to be found. We first indicated that hsa_circ_001895 predicted a poor prognosis in ccRCC patients. Additionally, overexpression of hsa_circ_001895 not only promoted cell proliferation, invasion and migration of ccRCC, but also inhibited cell apoptosis, whereas hsa_circ_001895 knockdown reversed the effect on ccRCC progression. In vivo s.c. xenotransplanted tumor model also showed that silencing hsa_circ_001895 could suppress in vivo ccRCC growth. Mechanistically, hsa_circ_001895 directly binds with microRNA (miR)‐296‐5p and inhibits its expression. Moreover, sex determining region Y (SRY)‐box 12 (SOX12) was identified as a target of miR‐296‐5p, the expression of which was suppressed by miR‐296‐5p. Notably, the inhibitory effect of hsa_circ_001895 on ccRCC progression was reversed by miR‐296‐5p inhibitor. In general, our findings indicated that hsa_circ_001895 may sponge miR‐296‐5p and promote SOX12 expression, which is the underlying mechanism of hsa_circ_001895‐induced ccRCC progression.

Prognostic role of the beta-2 adrenergic receptor in clear cell renal cell carcinoma

ABSTRACTThe beta-2 adrenergic receptor (ADRB2) regulates the proliferation, apoptosis, angiogenesis, migration, and metastasis of cancer cells. However, its function in the progression of clear cell renal cell carcinoma (ccRCC) is unknown. Here, we report that ADRB2 can be a novel prognostic factor for patients with ccRCC. The differential expression of ADRB2 in low-stage (stages I and II), high-stage (stages III and IV), low-grade (grades I and II), and high-grade (grades III and IV) ccRCC was identified in cohorts of patients from The Cancer Genome Atlas and the International Cancer Genome Consortium. We evaluated ADRB2 expression as a prognostic factor using the Kaplan-Meier survival curve, multivariate analysis, time-dependent area under the curve (AUC) of Uno’s C-index, and AUC of the receiver operating characteristics (ROC) at five years. Kaplan-Meier analysis revealed that reduced ADRB2 expression is associated with poor prognosis in ccRCC patients. Analysis of C-indices and AUC-ROC further confirmed this result. Moreover, multivariate analysis confirmed the prognostic significance of ADRB2 expression. Collectively, these findings suggest that ADRB2 is a potential prognostic factor for ccRCC.

A nomogram based on 9-lncRNAs signature for improving prognostic prediction of clear cell renal cell carcinoma

BackgroundAbnormal expressions of long noncoding RNAs (lncRNAs) are very common in clear cell renal cell carcinoma (ccRCC), and some of these have been reported to be highly correlated with prognosis of ccRCC patients.Methods“edgeR” AND “DEseq” R packages were used to explore differentially expressed genes (DEGs) between normal and tumor tissues of ccRCC samples from The Cancer Genome Atlas (TCGA). Univariable Cox survival analysis, robust likelihood-based survival model and multivariable Cox regression analysis were used to identify prognostic lncRNAs and construct lncRNAs signature. Finally, a graphic nomogram based on the lncRNAs signature was developed to predict 1-, 3- and 5-year survival probability of ccRCC patients by using rms R package.Results8413 DEGs including 2740 lncRNAs and 4530 mRNAs were identified between normal and tumor tissues. 395 lncRNAs were found to be associated with prognosis of ccRCC patients (P < 0.05). Among these 395 prognostic lncRNAs, 9 key prognostic lncRNAs (RP13-463N16.6, CTD-2201E18.5, RP11-430G17.3, AC005785.2, RP11-2E11.9, TFAP2A-AS1, RP11-133F8.2, RP11-297L17.2 and RP11-348J24.2) were identified by using robust likelihood-based survival model. A 9-lncRNAs signature was constructed by using estimated regression coefficients of the 9 key prognostic lncRNAs. Results of χ2-test or Fisher’s exact test indicated that the 9-lncRNAs signature was significantly associated with clinicopathological characteristics such as tumor grade, T stage, N stage, M stage, TNM stage and survival outcome of ccRCC patients. Multivariate analysis showed that the 9-lncRNAs signature, age and M stage were independent prognostic factors. Finally, a graphic nomogram based on the lncRNAs signature, age and M stage was developed to predict 1-, 3- and 5-year survival probability of ccRCC patients by using rms R package.ConclusionsA 9-lncRNAs signature associated with prognosis of ccRCC patients was constructed and a promising prognostic nomogram based on the 9-lncRNAs signature was developed for 1-, 3- and 5-year OS prediction of ccRCC patients in this study.

Clinical study on the relationship between serum interleukin-35 level and prognosis of patients with clear cell renal cell carcinoma

Objective To investigate the expression of IL-35 and determine its clinical significance in human clear cell renal cell carcinoma(ccRCC). Methods The levels of serum IL-35 in 132 patients with ccRCC and 100 healthy controls were detected by enzyme-linked immunosorbent assay (ELISA). Statistical analysis of the relationship between IL-35 levels and clinicopathological parameters and prognosis of patients with ccRCC. Results The serum IL-35 level in ccRCC patients (25.86 ± 11.78)pg / mL was significantly higher than that in healthy controls (10.05 ± 9.47) pg / mL, (P<0.001. Serum IL-35 levels were associated with pathological stage (P<0.001), fuhrman grade (P<0.001), tumor size (P=0.012), T stage (P=0.007), N stage (P=0.002) metastases (P<0.001) and recurrence (P=0.001). Kaplan-Meier survival analysis showed a significant correlation between high serum IL-35 levels and overall survival (log-rank, P<0.001). Multivariate analysis showed that serum IL-35 levels (HR=2.919, 95%CI=1.871-4.830, P=0.001) and pathological stage (HR=2.541, 95%CI=1.227-3.987, P=0.002) were independent prognostic factors for overall survival in ccRCC patients. Conclusions High levels of IL-35 are associated with poor prognosis in ccRCC patients. IL-35 may become a promising prognostic biomarker for ccRCC. Key words: Kidney Neoplasms; Interleukins; Prognosis

Dysregulation of the miR-25-IMPA2 axis promotes metastatic progression in clear cell renal cell carcinoma.

BackgroundThe molecular mechanism underlying clear cell renal cell carcinoma (ccRCC) metastasis remains unclear. We therefore aimed to elucidate the role of IMPA2 in ccRCC metastatic progression.MethodsUsing the Cancer Genome Atlas (TCGA) database and immunohistochemistry (IHC) staining, we investigated differences in IMPA2 mRNA and protein expression, as well as their clinical relevance, in ccRCC. To investigate the function of IMPA2 in ccRCC metastasis, we performed in vitro migration and in vivo lung colony-forming assays. We further explored the effect of microRNA (miR)-25 on IMPA2 expression by performing a luciferase reporter assay.FindingsWe show that ccRCC expresses relatively lower transcript levels of IMPA2 than normal kidney tissue. IMPA2 downregulation was greater in high-grade ccRCC than in low-grade ccRCC and was correlated with a poor prognosis in ccRCC patients. Importantly, we demonstrate that IMPA2 expression is inversely associated with the metastatic potential of ccRCC cells. We found that IMPA2 knockdown promotes, but overexpression suppresses, the cellular migration and lung colony-forming abilities of ccRCC cells. By using in silico and luciferase reporter assays, we found that IMPA2 expression is primarily influenced by miR-25 in ccRCC cells. Significantly, the inhibition of miR-25 function restored IMPA2 expression, thereby diminishing the metastatic potential of ccRCC cells.InterpretationWe conclude that miR-25-mediated IMPA2 downregulation constitutes a novel signature for cancer metastasis and poor outcomes in ccRCC. We further postulate that the therapeutic targeting of miR-25 can be useful for preventing the metastatic progression of ccRCC associated with IMPA2 downregulation.FundThis study was supported by the Ministry of Science and Technology, Taiwan (MOST 107-2314-B-038-094, MOST 106-2314-B-038-069-MY3, MOST 105-2320-B-038-021-MY3 and MOST 107-2320-B-038-056).

The Significance of Pregnancy-associated Plasma Protein a Serum Concentration in Clear Cell Renal Cell Carcinoma.

Proteinase pregnancy-associated plasma protein A (PAPP-A) modulates the cell growth and carcinogenesis process. Its role in clear cell renal cell carcinoma (ccRCC) remains unclear. This study aimed to evaluate the significance of PAPP-A serum concentration in diagnosis, follow-up and prognosis of ccRCC patients. In a prospective study including 121 patients who underwent radical or partial nephrectomy for ccRCC [localized ccRCC without relapse (n=80), localized ccRCC with later relapse (n=26), primary metastatic cancer (n=15)] PAPP-A serum concentration was assessed preoperatively and in certain subgroups also postoperatively. PAPP-A serum concentration showed no statistically significant difference between ccRCC and controls and among ccRCC subgroups, respectively. Disease stage and Fuhrman's grade were not shown to affect PAPP-A concentration. The dynamics of postoperative PAPP-A concentrations did not reveal any significance and PAPP-A was not a prognostic factor for cancer related or overall survival. PAPP-A serum concentration does not seem to be a useful biomarker in ccRCC.

Elevated CD36 expression correlates with increased visceral adipose tissue and predicts poor prognosis in ccRCC patients.

571 Background: Growing evidence has proved obesity one of the confirmed important etiologic indicators for renal cell carcinoma (RCC). CD36 is underpinned to be involved in adipose absorption, but its role in clear cell renal cell carcinoma (ccRCC) remains unclear. This study aimed to investigate the mRNA expression of CD36 in anthropometric measures of adipose tissue and defining its value in predicting prognosis in ccRCC patients. Methods: Real-Time qPCR was detected from 367 paired ccRCC and adjacent normal tissues. Distributions of categorical clinical-pathological data together with levels of CD36 expression were compared with χ2-test. Subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) were measured by MRI. Pearson’s correlation coefficient was utilized to quantify relations between body mass index (BMI), VAT%, SAT and CD36 expression respectively. Cox regression analysis were developed to address the influence of independent factors on prognostic value. Gene Set Enrichment Analysis (GSEA) was performed to select related genes and pathways from TCGA database. Results: In the current study, we demonstrated that CD36 mRNA was highly expressed in ccRCC tissues, and was found significantly increased in patients with advanced TNM stage ( p= 0.003, p&lt; 0.001, p&lt; 0.001), and high VAT% ( p= 0.004). Pearson’s correlation coefficient indicated CD36 amplification positively correlated with BMI ( r= 0.117, p= 0.025), VAT% ( r= 0.465, p&lt; 0.001), while negatively with SAT ( r= -0.296, p= 0.002). Furthermore, ccRCC patients with elevated CD36 expression held shorter PFS and OS, with HR of 4.873 (3.300-7.196, p&lt; 0.001) and 4.610 (2.956-7.189, p&lt; 0.001). In 104 cases whose MRI scans were available, VAT was significantly correlated with poor PFS and OS. Significant genes were obtained from GSEA, and CD36 was found involved in the most significant pathways including fatty acid metabolism, angiogenesis and TGF-β signaling pathways. Conclusions: In conclusion, our study first reveal that elevated CD36 mRNA expression is positively correlated to distribution of abdominal adipose, particularly VAT%, which, in addition, notably predicts poor prognosis in ccRCC patients.

124 - Elevated CD36 expression correlates with increased visceral adipose tissue and predicts poor prognosis in ccRCC patients

124 - Elevated CD36 expression correlates with increased visceral adipose tissue and predicts poor prognosis in ccRCC patients

Elevated CD36 expression correlates with increased visceral adipose tissue and predicts poor prognosis in ccRCC patients.

Objective: Growing evidence has proved obesity one of the confirmed important etiologic indicators for renal cell carcinoma (RCC). CD36 is underpinned to be involved in adipose absorption, but its role in clear cell renal cell carcinoma (ccRCC) remains unclear. This study aimed to investigate the mRNA expression of CD36 in anthropometric measures of adipose tissue and defining its value in predicting prognosis in ccRCC patients.Methods: Real-Time qPCR gene expression analysis was detected from 367 paired ccRCC and adjacent normal tissues. Distributions of categorical clinical-pathological data together with levels of CD36 expression were compared with χ2-test in a contingency table. Subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) were measured by magnetic resonance imaging (MRI) and identified at the level of the umbilicus. Pearson's correlation coefficient was utilized to quantify relations between body mass index (BMI), VAT%, SAT and CD36 expression respectively. Partial likelihood test from univariate and multivariate Cox regression analysis were developed to address the influence of independent factors on progression-free survival (PFS) and overall survival (OS). The Kaplan-Meier method and log-rank test were performed to assess the survival benefits between discrete levels.Results: In the current study, CD36 mRNA was demonstrated highly expressed in ccRCC compared with normal tissues. In addition, CD36 mRNA expression was significantly increased in patients with advanced TNM stage (p=0.003, p<0.001, p<0.001), and high VAT% (p=0.004). Pearson's correlation coefficient indicated that CD36 amplification positively correlated with BMI (r=0.117, p=0.025), VAT% (r=0.465, p<0.001), while negatively associated with SAT (r=-0.296, p=0.002). Median PFS was 60 months and OS was 99 months. Meanwhile, ccRCC patients with elevated CD36 expression held shorter PFS and OS, with hazard ratios [HR; 95% confidence interval (CI)] of 4.873 (3.300-7.196, p<0.001) and 4.610 (2.956-7.189, p<0.001). In 104 cases with available MRI scans, VAT was significantly correlated with poor PFS and OS, with HR of 2.556 (1.036-6.310, p<0.042) and 3.291 (1.034-10.477, p<0.044). A total of 100 significant genes were obtained from GSEA, and CD36 was found involved in the most significant pathways including fatty acid metabolism, UV response, angiogenesis and transforming growth factor beta (TGF-β) signaling pathways.Conclusion: In conclusion, our study first reveal that elevated CD36 mRNA expression is positively correlated to distribution of abdominal adipose, particularly VAT%, which, in addition, notably predicts poor prognosis in ccRCC patients.

Overexpression of FZD1 is Associated with a Good Prognosis and Resistance of Sunitinib in Clear Cell Renal Cell Carcinoma.

Frizzled class receptor 1 (FZD1), a receptor for Wnt signaling pathway. Overexpression of FZD1 has been detected in many cancer tissues and cells resulting in tumor development and drug resistance. However, its expression status and prognostic merit in renal cancer still remains unclear. We screened the FZD1 mRNA in clear cell renal cell carcinoma (ccRCC) and papillary renal cell carcinoma (pRCC) from TCGA database and Oncomine database. We then detected FZD1 mRNA expression in sunitinib-resistant cells and the corresponding parental cells by qRT-PCR. FZD1 level was significantly upregulated in renal cancer tissues, renal cancer cell lines and their corresponding sunitinib-resistant cells. FZD1 level was also associated with the clinicopathological characteristics of ccRCC patients that could discriminate metastasis, pathological stage, recurrence and prognosis in ccRCC patients. The Kaplan-Meier survival curve and the log-rank test revealed FZD1 was higher in lower clinical stage and grade that correlated with better overall survival (OS) and disease-free survival (DFS) in total and subgroups of ccRCC patients. Both univariate and multivariate cox regression analysis indicated that high FZD1 level was an independent predictor of good prognosis for OS (HR 0.569, P=0.001) and DFS (HR 0.559, P=0.036) in ccRCC patients. Using cBioportal program, less than 1% mutation in the patients with renal cancer was observed, the alterations in FZD1 were correlated with better OS (P=0.0404) in ccRCC patients. Finally, the result of KEGG pathway analysis predicted seven potential pathways that FZD1 and its related genes got involved in ccRCC, including Hippo signaling pathway. This indicated potential therapeutic targets of ccRCC. In conclusion, our results suggested that expression status of FZD1 had a diagnostic value and prognostic value in ccRCC patients, it also may serve as a potential drug target to relieve sunitinib resistance in renal cancer patients.

NLRC5 mediates cell proliferation, migration, and invasion by regulating the Wnt/β-catenin signalling pathway in clear cell renal cell carcinoma

NLRC5, a newly discovered member of the NLR family, has been reported to regulate immune responses and promote cell proliferation, migration, and invasion in hepatocellular carcinoma. However, to date, the potential regulatory roles and molecular mechanisms by which NLRC5 affects the development and progression of clear cell renal cell carcinoma (ccRCC) remain largely unknown. In this study, human clinical data from The Cancer Genome Atlas database revealed that increased NLRC5 expression was associated with advanced stage and poor prognosis in ccRCC patients. Moreover, experimental results showed that NLRC5 is aberrantly overexpressed in human ccRCC tissues and cell lines. Depletion of NLRC5 attenuated ccRCC cell proliferation, migration, and invasion and suppressed ccRCC growth in a nude mouse model. By contrast, overexpression of NLRC5 promoted the proliferation, migration, and invasion of ccRCC cells in vitro. Additionally, NLRC5 expression is not only positively correlated with β-catenin but also coordinates the activation of the downstream Wnt/β-catenin signalling pathway. Together, our data suggest that NLRC5 may be a potential therapeutic target for ccRCC therapy.

Downregulation of CLDN7 due to promoter hypermethylation is associated with human clear cell renal cell carcinoma progression and poor prognosis

BackgroundMetastasis is the primary cause of death in renal cell carcinoma (RCC). Loss of cell-to-cell adhesion, including tight junctions (TJs) is the initial step in the process of metastasis. Claudin-7 (CLDN7) is a major component of TJs. However, the clinical significance and its regulation of kidney tumorigenesis remain poorly understood.MethodsA total of 120 fresh clear cell RCC (ccRCC) specimens and 144 primary RCC and adjacent nonmalignant renal paraffin specimens were obtained from Department of Urology, Peking University First Hospital. Expression of CLDN7 in ccRCC tissues and cell lines were determined using bioinformatic data mining, quantitative real-time PCR (qRT-PCR), Western blotting and immunostaining. The clinical significance of CLDN7 expression and promoter DNA methylation status was analyzed in ccRCC patients from Peking University First Hospital and The Cancer Genome Atlas. Additionally, the methylation specific-PCR, bisulfite genomic sequencing and demethylation analysis of CLDN7 were performed. Biological functions of CLDN7 were investigated by examining cell proliferation using MTS assays and EdU incorporation assays, cell migration by in vitro wound healing assays and transwell migration assays, cell invasion by transwell invasion assays, and cell apoptosis by flow cytometry. Mouse model experiments were performed to confirm the effects of CLDN7 on tumor growth and metastasis in vivo. The molecular mechanism of CLDN7 function was investigated using gene-set enrichment analysis (GSEA) and high-throughput cDNA sequencing (RNA-Seq) and confirmed by qRT-PCR, Western blot and immunostaining in vitro and in vivo.ResultsOur findings revealed that CLDN7 is frequently downregulated via hypermethylation of its promoter in ccRCC. CLDN7 can help predict aggressive tumor status and poor prognosis in ccRCC patients. Interestingly, hypermethylation of the CLDN7 promoter was related to advanced ccRCC status and poor prognosis. Moreover, overexpression of CLDN7 induced cell apoptosis, suppressed proliferation, migration and invasion abilities of ccRCC cells both in vitro and in vivo. Additionally, GSEA and RNA-Seq results showed that CLDN7 had negative effects in cancer-associated signaling pathways and (epithelial-mesenchymal transition) EMT-related pathways. These results were validated by qRT-PCR, Western blot and immunostaining.ConclusionsWe have demonstrated a previously undescribed role of CLDN7 as a ccRCC suppressor and suggest that loss of CLDN7 potentiates EMT and tumor progression. CLDN7 may serve as a functional tumor suppressor in tumor progression and a potential biomarker and target in patients with ccRCC.

Decreased expression of BRAF-activated long non-coding RNA is associated with the proliferation of clear cell renal cell carcinoma

BackgroundBRAF-activated long non-coding RNA (BANCR) has been associated with various types of cancer. Nevertheless, the role of BANCR in clear cell renal cell carcinoma (ccRCC) is still not fully understood. This study aims to investigate the relationship between ccRCC and BANCR.MethodsExpression of BANCR in TCGA renal cancer data sets was analyzed. The expression pattern of BANCR in Immortalized normal human proximal tubule epithelial cell line HK-2 and ccRCC cell lines (ACHN, CAKI-1, A498 and 786-O) was detected by real-time quantitative RT-PCR (qRT-PCR). ccRCC tissues with adjacent normal renal tissues diagnosed by pathological methods from 62 patients were used to detect the expression of BANCR, and its correlation with prognosis of ccRCC patients was assessed by Kaplan-Meier method. The LV-BANCR vector was used to examine the influence of BANCR on the proliferation, migration, invasion, apoptosis and cell cycle distribution of ccRCC cells in vitro.ResultsBANCR was downregulated in renal cancer according to TCGA data sets. Compared with adjacent normal renal tissues and normal human proximal tubule epithelial cell line HK-2, BANCR expression was significantly decreased in ccRCC tissues and ccRCC cell lines, and its low expression was associated with poor prognosis. Moreover, in the condition of BANCR overexpression by LV-BANCR vector, the proliferation, migration, invasion capacity of ccRCC cells was inhibited, while the apoptosis was increased and the G1 cell cycle arrest was induced in vitro.ConclusionsBANCR is downregulated in ccRCC tissues and cell lines, and is associated with ccRCC progression. Thus, BANCR may represent a novel prognostic biomarker and a potential therapeutic target for ccRCC patients.

GAMBLING DISORDER: PERSONALITY CHARACTERISTICS IN A CLINICAL SAMPLE

Clear cell renal cell carcinoma (cc-RCC), is a serious cancer regarding; its fatality, liability for metastases and chemoresistance, so identification of recent therapeutic targets to improve the patients prognosis is needed. SPOP is a BTB/POZ domain containing speckle-type POZ protein, has been identified as an E3 ubiquitin ligase component. ZEB1 is an essential epithelial mesenchymal transition (EMT) activator; E-cadherin is a cell adhesion protein that had been detected in normal epithelial cells membrane.Was to assess the tissue protein markers SPOP, ZEB1 & E-cadherin expressions in benign areas of neoplastic kidney specimens and in cc-RCC patients, then correlating their expression levels with patients clinicopathological and prognostic data.We evaluated SPOP, ZEB-1 & E-cadherin expression using immunohistochemistry in samples from 50 cc-RCC and 20 benign areas of neoplastic kidney specimens, then we followed our patients for 5 years and finally we have analyzed correlations between the levels of markers expressions with patients clinicopathological and prognostic criteria in cc-RCC.Positive expression of SPOP & ZEB1 in addition to negative E- cadherin expression was detected in cc-RCC more than benign areas of neoplastic kidney specimens (p = 0.004 and p < 0.001 respectively). In cc-RCC Positive expression of SPOP, ZEB1 and negative E- cadherin expression was associated with higher grade (p = 0.006, 0.007 & <0.001 respectively), advanced AJCC stage (p = 0.013, 0.023 & <0.001 respectively), presence of L.N metastases (p = 0.002 = 0.010 and <0.001 respectively), distant metastases (p = 0.001, 0.003 & 0.035 respectively), poor PFS and OS rates (p < 0.001 and p = 0.013 respectively).Positive expression of SPOP& ZEB1 in addition to negative E- cadherin are associated with poor prognosis in cc-RCC patients.

Low level of isocitrate dehydrogenase 1 predicts unfavorable postoperative outcomes in patients with clear cell renal cell carcinoma

BackgroundThe purpose of this study was to investigate the role of isocitrate dehydrogenase 1 (IDH1) expression on prognosis of patients with clear cell renal cell carcinoma (ccRCC) following nephrectomy.MethodsWe retrospectively enrolled 358 ccRCC patients undergoing nephrectomy in Renji Hospital. Clinicopathologic features, overall survival (OS) and recurrence-free survival (RFS) of ccRCC patents were all collected. IDH1 expression level was assessed by immunohistochemistry and its association with clinicopathologic features and outcomes were also evaluated. Kaplan-Meier method with the log-rank test was applied to compare survival curves. Multivariate cox regression models were applied to analyze the prognostic value of each factor on OS and RFS of ccRCC patients. Moreover, two nomograms with factors selected by multivariate analysis were constructed to evaluate the prognosis of ccRCC patients, and the calibration plots were built to assess the predictive accuracy of nomograms.ResultsOur data indicated that IDH1 expression level was down-regulated in ccRCC tissues, and it negatively correlated with tumor Fuhrman grade (p = 0.025). Low IDH1 expression was associated with worse OS and RFS for cccRCC patients (OS, p = 0.004; RFS, p = 0.03). In addition, IDH1 could significantly stratify patients’ OS and RFS in intermediate/high risk patients (UISS score ≥ 4) (p = 0.049 and p = 0.004, respectively). Furthermore, incorporating IDH1 with other prognostic factors could predict ccRCC patients’ OS and RFS (OS, c-index = 0.779; RFS, c-index = 0.798) and perform better than TNM and SSIGN system.ConclusionsLow IDH1 expression level might be an adverse prognostic biomarker for clinical outcomes of ccRCC patients, and two nomograms with IDH1 are potential effective prognostic models for ccRCC.

SPOP, ZEB-1 and E-cadherin expression in clear cell renal cell carcinoma (cc-RCC): Clinicopathological and prognostic significance

BackgroundClear cell renal cell carcinoma (cc-RCC), is a serious cancer regarding; its fatality, liability for metastases and chemoresistance, so identification of recent therapeutic targets to improve the patients prognosis is needed. SPOP is a BTB/POZ domain containing speckle-type POZ protein, has been identified as an E3 ubiquitin ligase component. ZEB1 is an essential epithelial mesenchymal transition (EMT) activator; E-cadherin is a cell adhesion protein that had been detected in normal epithelial cells membrane. AimWas to assess the tissue protein markers SPOP, ZEB1 & E-cadherin expressions in benign areas of neoplastic kidney specimens and in cc-RCC patients, then correlating their expression levels with patients clinicopathological and prognostic data. MethodsWe evaluated SPOP, ZEB-1 & E-cadherin expression using immunohistochemistry in samples from 50 cc-RCC and 20 benign areas of neoplastic kidney specimens, then we followed our patients for 5 years and finally we have analyzed correlations between the levels of markers expressions with patients clinicopathological and prognostic criteria in cc-RCC. ResultsPositive expression of SPOP & ZEB1 in addition to negative E- cadherin expression was detected in cc-RCC more than benign areas of neoplastic kidney specimens (p = 0.004 and p < 0.001 respectively). In cc-RCC Positive expression of SPOP, ZEB1 and negative E- cadherin expression was associated with higher grade (p = 0.006, 0.007 & <0.001 respectively), advanced AJCC stage (p = 0.013, 0.023 & <0.001 respectively), presence of L.N metastases (p = 0.002 = 0.010 and <0.001 respectively), distant metastases (p = 0.001, 0.003 & 0.035 respectively), poor PFS and OS rates (p < 0.001 and p = 0.013 respectively). ConclusionPositive expression of SPOP& ZEB1 in addition to negative E- cadherin are associated with poor prognosis in cc-RCC patients.

PD57-12 THE PROGNOSTIC VALUE OF PROGRAMMED DEATH-LIGAND 1 IN A CHINESE COHORT WITH CLEAR CELL RENAL CELL CARCINOMA

You have accessJournal of UrologyKidney Cancer: Advanced (including Drug Therapy) III1 Apr 2018PD57-12 THE PROGNOSTIC VALUE OF PROGRAMMED DEATH-LIGAND 1 IN A CHINESE COHORT WITH CLEAR CELL RENAL CELL CARCINOMA Yuan-Yuan Qu, Wen-Jun Xiao, Hai-Liang Zhang, and Ding-Wei Ye Yuan-Yuan QuYuan-Yuan Qu More articles by this author , Wen-Jun XiaoWen-Jun Xiao More articles by this author , Hai-Liang ZhangHai-Liang Zhang More articles by this author , and Ding-Wei YeDing-Wei Ye More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.2656AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Programmed death -1 (PD-1) and its ligand programmed death -ligand 1 (PD-L1) have become research hotspots in recent years. New immunotherapies targeting the PD-1/PD-L1 axis were reported to give promising clinical responses in patients with various types of cancer, including renal cell carcinoma (RCC). This study aimed to explore the prognostic value of PD-L1 mRNA expression in tumor tissues for patients with clear cell RCC (ccRCC). METHODS This study enrolled 367 patients treated with radical nephrectomy for ccRCC during the period of 2008 to 2015. Real-time polymerase chain reaction was performed to detect the expression level of PD-L1 in paired cancer tissue and adjacent normal tissue. The relative expression of PD-L1 in ccRCC was measured using the ratio of PD-L1 expression in ccRCC/matched normal tissues. “Low, middle, and high PD-L1 expression” denotes the ratio of PD-L1 mRNA expression in ccRCC/matched normal tissues of less than 1, greater than 1 and less than 3, and greater than 3, respectively. Cox regression models were used to evaluate the prognostic value of all parameters. RESULTS 41 (11.2%), 160 (43.6%) and 166 (45.2%) patients showed low, middle and high expression of PD-L1, respectively. Patients with high PD-L1 expression were more likely to exhibit adverse pathologic features including larger tumor size (P=0.042), advanced T stage (P=0.034), lymph node metastasis (P=0.005), and distant metastasis (P<0.001). High PD-L1 expression comprised 77.5% (31/42) and 60.6% (20/33) of the subgroup with stage IV and grade 4, respectively, while low PD-L1 expression comprised 0% (0/42) and 6.1% (2/33) of the subgroup with stage IV and grade 4, respectively. The multivariate analyses revealed that high or middle PD-L1 expression, lymph node metastasis, distant metastasis, and poor tumor grade were independent prognostic factors of shorter progression-free survival (PFS). Moreover, high or middle PD-L1 expression, advanced T stage, lymph node metastasis, and distant metastasis maintained a significant predictive role for overall survival (OS) after adjusting for covariants. The median PFS for patients with low, middle and high expression of PD-L1 were 86 months (95% CI: 75.1–96.9), 59 months (95% CI: 46.5–71.5) and 50 months (95% CI: 39.7–60.3), respectively. The Kaplan-Meier curves of OS stratified by PD-L1 expression also showed statistically significant difference (P=0.001). CONCLUSIONS Our data suggested that expression of PD-L1 in ccRCC tissue was correlated with prognosis of ccRCC patients. Targeting the PD-1/PD-L1 pathway should be considered in the treatment of ccRCC patients. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e1071-e1072 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Yuan-Yuan Qu More articles by this author Wen-Jun Xiao More articles by this author Hai-Liang Zhang More articles by this author Ding-Wei Ye More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

FOXK2 suppresses the malignant phenotype and induces apoptosis through inhibition of EGFR in clear-cell renal cell carcinoma.

Forkhead box K2 (FOXK2) belongs to the forkhead box transcription factor family. Recent studies have revealed that FOXK2 plays essential roles in cancer cell proliferation and survival. However, the biological function of FOXK2 in renal cell carcinoma remains unexplored. In our study, we demonstrated that FOXK2 mRNA and protein levels were decreased in clear-cell renal cell carcinoma (ccRCC) tissues compared to those in corresponding non-tumor renal tissues, and decreased FOXK2 levels were associated with poor prognosis in ccRCC patients after nephrectomy. FOXK2 suppressed proliferation, migration and invasion capabilities of ccRCC cells and induced cellular apoptosis in vitro. Moreover, we found that FOXK2 overexpression inhibited xenograft tumor growth and promoted apoptosis in vivo. Genome-wide transcriptome profiling using FOXK2 overexpressed 769-P cells revealed that the epidermal growth factor receptor (EGFR) was a potential downstream gene of FOXK2. Overexpression of EGFR is able to rescue the inhibited proliferation capacity and the enhanced apoptosis capacity due to the overexpression of FOXK2 in 769-P cells. Collectively, our results indicate that FOXK2 inhibits the malignant phenotype of ccRCC and acts as a tumor suppressor possibly through the inhibition of EGFR.

Low neighbor of Brca1 gene expression predicts poor clinical outcome and resistance of sunitinib in clear cell renal cell carcinoma.

ObjectiveTo study the expression of Neighbor of Brca1 gene (NBR1) in clear cell renal cell carcinoma (ccRCC), renal cancer cells and the chemoresistance cells and to elucidate its clinical prognostic and chemoresistance value.Materials and MethodsWe screened the NBR1 mRNA in ccRCC from The Cancer Genome Atlas (TCGA) database and examined expression levels of NBR1 mRNA in 48 cases of ccRCC tissues, renal cancer cell lines and chemoresistance cells by qRT-PCR. Then, we extended two additional data sets in oncomine datebase (https://www.oncomine.org) to further confirm the results of the TCGA database. Immunohistochemistry (IHC) assay data performed in ccRCC tissues and normal tissues were downloaded from The Human Protein Atlas.ResultsThe mRNA levels of NBR1 were downregulated in TCGA-KIRC database (n = 533) and ccRCC patient samples (n=48) as well as in RCC cell lines and their chemoresistance cells. Similarly, the protein levels of NBR1 were lower in ccRCC patient samples. NBR1 level was associated with the clinical pathological stage and could discriminate metastasis, recurrence and prognosis in ccRCC patients. Low level of NBR1 mRNA showed a significance poor prognostic of overall survival (OS), disease–free survival (DFS) with univariate and multivariate analyses in ccRCC patients and sunitinib resistance.ConclusionsTaken together, our results suggest that low level of NBR1 can predict poor clinical outcome and resistance of sunitinib in patients with ccRCC.