Prognostic Factor For ccRCC Patients Research Articles

Comprehensive analysis of LD-related genes signature for predicting prognosis and immunotherapy response in clear cell renal cell carcinoma

BackgroundLipid droplets (LD) in renal clear cell carcinoma (ccRCC)play a crucial role in lipid metabolism and immune response modulation. The purpose of this study was to create a LD-related signature to predict prognosis and guide the immunotherapy and targeted therapy in ccRCC patients.MethodsWe conducted a comprehensive analysis using transcriptional profiles and clinical data obtained from The Cancer Genome Atlas (TCGA). LD-related genes were identified from existing literature and the GeneCards database, and differentially expressed genes were determined. Sequentially, we conducted Cox regression analysis and Lasso regression analysis, to establish a prognostic risk model. The performance of the risk model was evaluated using Kaplan–Meier (KM) analysis and time-dependent receiver operating characteristic (ROC) analysis. Additionally, gene set enrichment analysis (GSEA), ESTIMATE, CIBERSORT, and immunophenoscore (IPS) algorithm were used to assess the tumor microenvironment (TME) and treatment response.ResultsWe constructed a risk signature with four LD-related genes in the TCGA dataset, which could be an independent prognostic factor in ccRCC patients. Then, patients were classified into two risk groups and exhibited notable differences in overall survival (OS), progression-free survival (PFS), and TME characteristics. Furthermore, we developed a comprehensive nomogram based on clinical features, which demonstrated good prognostic predictive value. According to the results of GSEA analysis, immune-related pathways were found to be significantly enriched in the high-risk group. Additionally, the high-risk group displayed high levels of immune cell infiltration, TMB and IPS scores, indicating better efficacy of immune checkpoint inhibitors (ICIs). Finally, high-risk demonstrated reduced IC50 values compared to the low-risk counterpart for specific targeted and chemotherapeutic drugs, suggesting that the patients receiving these targeted drugs in high-risk group had better treatment outcomes.ConclusionsOur findings suggested that the LD-related gene signature could potentially predict the prognosis of ccRCC patients. Additionally, it showed promise for predicting responses to immunotherapy and targeted therapy in ccRCC patients. These insights might potentially have guided the clinical management of these patients, but further validation and broader data analysis are needed to confirm these preliminary observations.

Identification of prognostic RNA editing profiles for clear cell renal carcinoma.

Clear cell renal cell carcinoma (ccRCC) is the most common type of renal cancer and currently lacks effective biomarkers. This research aims to analyze and identify RNA editing profile associated with ccRCC prognosis through bioinformatics and in vitro experiments. Transcriptome data and clinical information for ccRCC were retrieved from the TCGA database, and RNA editing files were obtained from the Synapse database. Prognostic models were screened, developed, and assessed using consistency index analysis and independent prognostic analysis, etc. Internal validation models were also constructed for further evaluation. Differential genes were investigated using GO, KEGG, and GSEA enrichment analyses. Furthermore, qPCR was performed to determine gene expression in human renal tubular epithelial cells HK-2 and ccRCC cells A-498, 786-O, and Caki-2. An RNA editing-based risk score, that effectively distinguishes between high and low-risk populations, has been identified. It includes CHD3| chr17:7815229, MYO19| chr17:34853704, OIP5-AS1| chr15:41590962, MRI1| chr19:13883962, GBP4| chr1:89649327, APOL1| chr22:36662830, FCF1| chr14:75203040 edited sites or genes and could serve as an independent prognostic factor for ccRCC patients. qPCR results showed significant up-regulation of CHD3, MYO19, MRI1, APOL1, and FCF1 in A-498, 786-O, and Caki-2 cells, while the expression of OIP5-AS1 and GBP4 was significantly down-regulated. RNA editing site-based prognostic models are valuable in differentiating between high and low-risk populations. The seven identified RNA editing sites may be utilized as potential biomarkers for ccRCC.

Development and validation of a combined hypoxia- and metabolism-related prognostic signature to predict clinical prognosis and immunotherapy responses in clear cell renal cell carcinoma.

Hypoxia and metabolism are closely correlated with the progression of cancer. We aimed to construct a combined hypoxia- and metabolism-related genes (HMRGs) prognostic signature to predict survival and immunotherapy responses in patients with clear cell renal cell carcinoma (ccRCC). The RNA-seq profiles and clinical data of ccRCC were acquired from the TCGA and the ArrayExpress (E-MTAB-1980) databases. Least absolute shrinkage and selection operator (LASSO) and univariate and multivariate Cox regression analyses were applied to establish a prognostic signature. The E-MTAB-1980 cohort was selected for validation. The effectiveness and reliability of the signature were further evaluated by Kaplan-Meier (K-M) survival and time-dependent receiver operating characteristic (ROC) curves. Further analyses, including functional enrichment, ssGSEA algorithm, CIBERSORT algorithm, and expression of immune checkpoints, were explored to investigate immune status and immunotherapy responses. We constructed a prognostic eight-gene signature with IRF6, TEK, PLCB2, ABCB1, TGFA, COL4A5, PLOD2, and TUBB6. Patients were divided into high-risk and low-risk groups based on the medium-risk score. The K-M analysis revealed that patients in the high-risk group had an apparently poor prognosis compared to those in the low-risk group in the TCGA (p < 0.001) and E-MTAB-1980 (p < 0.005). The area under ROC curve (AUC) of the prognostic signature was 0.8 at 1 year, 0.77 at 3 years, and 0.78 at 5 years in the TCGA, respectively, and was 0.82 at 1 year, 0.74 at 3 years, and 0.75 at 5 years in the E-MTAB-1980, respectively. Independent prognostic analysis confirmed the risk score as a separate prognostic factor in ccRCC patients (p < 0.001). The results of ssGSEA showed not only a high degree of immune cell infiltration but also high scores of immune-related functions in the high-risk group. The CIBERSORT analysis further confirmed that the abundance of immune cells was apparently different between the two risk groups. The risk score was significantly correlated with the expression of cytotoxic T lymphocyte-associated antigen-4 (CTLA4), lymphocyte-activation gene 3 (LAG3), and programmed cell death protein 1 (PD-1). The HMRGs signature could be used to predict clinical prognosis, evaluate the efficacy of immunotherapy, and guide personalized immunotherapy in ccRCC patients.

Development and validation of a novel anoikis-related gene signature in clear cell renal cell carcinoma.

Despite numerous treatments available, clear cell renal cell carcinoma (ccRCC) remains a deadly and invasive cancer. Anoikis-related genes (ARGs) are essential regulators of tumor metastasis and development. However, the potential roles of ARGs in ccRCC remain unclear. Based on the TCGA-KIRC cohort and GeneCards database, we identified differentially expressed ARGs in ccRCC. Then a 4 ARGs risk model was created by Cox regression and LASSO. The Kaplan-Meier and receiver operating characteristic (ROC) curves were utilized to verify the predictive efficacy of the prognostic signature. Subsequently, the possible molecular mechanism of ARGs was investigated by functional enrichment analysis. To assess the immune infiltration, immune checkpoint genes, and immune function in various risk groups, single sample gene set enrichment (ssGSEA) algorithm was employed. Furthermore, the low-risk and high-risk groups were compared in terms of tumor mutation burden (TMB). Ultimately, we analyzed the protein expression of these four ARGs utilizing the western blot test. Four genes were utilized to create a risk signature that may predict prognosis, enabling the classification of KIRC patients into groups with low or high risk. The reliability of the signature was examined utilizing survival analysis and ROC analysis. According to the multivariate Cox regression result, the risk score was a reliable independent prognostic predictor for KIRC patients. The novel risk model could differentiate between KIRC patients with various clinical outcomes and represent KIRC's specific immune status. An analysis of the correlation of TMB and risk score indicated a positive correlation between them, with high TMB being potentially linked to worse outcomes. Based on our findings, the prognostic signature of ARGs may be employed as an independent prognostic factor for ccRCC patients. It may introduce alternative perspectives on prognosis evaluation and serve as a prominent reference for personalized and precise therapy in KIRC.

Comprehensive analysis of prognostic value, immune implication and biological function of CPNE1 in clear cell renal cell carcinoma.

Background: Elevated expression of Copine-1 (CPNE1) has been proved in various cancers; however, the underlying mechanisms by which it affects clear cell renal cell carcinoma (ccRCC) are unclear. Methods: In this study, we applied multiple bioinformatic databases to analyze the expression and clinical significance of CPNE1 in ccRCC. Co-expression analysis and functional enrichment analysis were investigated by LinkedOmics, cBioPortal and Metascape. The relationships between CPNE1 and tumor immunology were explored using ESTIMATE and CIBERSORT method. In vitro experiments, CCK-8, wound healing, transwell assays and western blotting were conducted to investigate the effects of gain- or loss-of-function of CPNE1 in ccRCC cells. Results: The expression of CPNE1 was notably elevated in ccRCC tissues and cells, and significantly correlated with grade, invasion range, stage and distant metastasis. Kaplan-Meier and Cox regression analysis displayed that CPNE1 expression was an independent prognostic factor for ccRCC patients. Functional enrichment analysis revealed that CPNE1 and its co-expressed genes mainly regulated cancer-related and immune-related pathways. Immune correlation analysis showed that CPNE1 expression was significantly related to immune and estimate scores. CPNE1 expression was positively related to higher infiltrations of immune cells, such as CD8+ T cells, plasma cells and regulatory T cells, exhibited lower infiltrations of neutrophils. Meanwhile, elevated expression of CPNE1 was characterized by high immune infiltration levels, increased expression levels of CD8+ T cell exhaustion markers (CTLA4, PDCD1 and LAG3) and worse response to immunotherapy. In vitro functional studies demonstrated that CPNE1 promoted proliferation, migration and invasion of ccRCC cells through EGFR/STAT3 pathway. Conclusion: CPNE1 is a reliable clinical predictor for the prognosis of ccRCC and promotes proliferation and migration by activating EGFR/STAT3 signaling. Moreover, CPNE1 significantly correlates with immune infiltration in ccRCC.

Tumoral Overexpression of Hepcidin is Associated with Poor Prognosis of Patients with Clear Cell Renal Cell Carcinoma

This study aimed to investigate the prognostic value of tumoral HAMP expression in patients with clear cell renal cell carcinoma (ccRCC). In a TCGA dataset, we found that HAMP mRNA expression was increased in ccRCC tumors compared with normal controls. Tumoral HAMP mRNA expression was positively correlated with clinical stage, tumor grade, and TNM stages. Patients with high HAMP expression had poorer overall survival than those with low HAMP expression. Tumoral HAMP mRNA level independently predicted the survival of patients. HAMP protein expression was increased in real-world ccRCC tumors compared with those in paired, adjacent noncancerous tissue and was positively correlates with tumor grading. These results suggest HAMP as a potential prognostic factor for ccRCC patients.

A comprehensive analysis of the prognostic value and immune infiltration of low expression DBT in clear cell renal cell carcinoma.

Background: Although DBT is strongly associated with human tumorigenesis and progression through a variety of pathways, the role of DBT in clear cell renal cell carcinoma (ccRCC) has not been well established. Materials and methods: The Cancer Genome Atlas (TCGA)-Kidney renal clear cell carcinoma (KIRC) databset provides RNA sequencing data and clinicopathological information on ccRCC. The Gene Expression Omnibus (GEO) database was used to validate the DBT expression levels, and qPCR was used to examine the DBT expression in renal cancer cell lines and ccRCC tissue samples from our centre. In parallel, DBT protein expression was explored in the Human Protein Atlas (HPA) database, and western blotting and immunohistochemistry of renal cancer cell lines and ccRCC tissues validated the results. Additionally, the diagnostic and prognostic value of DBT was comprehensively evaluated by receiver operating characteristic (ROC) curves, univariate and multivariate Cox regression analyses, and Kaplan‒Meier survival analysis. The protein‒protein interaction (PPI) network based on the STRING website, Gene Ontology (GO) analysis, Kyoto Gene and Genome Encyclopedia (KEGG) analysis and gene set enrichment analysis (GSEA) further provided a landscape of the molecular mechanisms of DBT in ccRCC. Finally, the TIMER 2.0, GEPIA and TISIDB websites were used to understand the relationship between DBT and immune characteristics. Results: The mRNA expression and protein expression of DBT were significantly downregulated in ccRCC tissues relative to normal tissues, which was associated with poor clinical outcomes. DBT has an encouraging discriminatory power for ccRCC and is an independent prognostic factor for ccRCC patients. Mechanistically, DBT is mainly involved in the regulation of immune-related signalling pathways in ccRCC; it is associated with a variety of immune infiltrating cells and immune checkpoints. Conclusion: DBT is a tumour suppressor gene in ccRCC and could be used as a new biomarker for diagnostic and prognostic purposes, and it is associated with immune infiltration in ccRCC.

A Five Collagen-Related Gene Signature to Estimate the Prognosis and Immune Microenvironment in Clear Cell Renal Cell Cancer.

Collagen is the main component of the extracellular matrix (ECM) and might play an important role in tumor microenvironments. However, the relationship between collagen and clear cell renal cell cancer (ccRCC) is still not fully clarified. Hence, we aimed to establish a collagen-related signature to predict the prognosis and estimate the tumor immune microenvironment in ccRCC patients. Patients with a high risk score were often correlated with unfavorable overall survival (OS) and an immunosuppressive microenvironment. In addition, the collagen-related genetic signature was highly correlated with clinical pathological features and can be considered as an independent prognostic factor in ccRCC patients. Moreover, GSEA results show that patients with a high risk grade tend to be associated with epithelial–mesenchymal junctions (EMT) and immune responses. In this study, we developed a collagen-related gene signature, which might possess the potential to predict the prognosis and immune microenvironment of ccRCC patients and function as an independent prognostic factor in ccRCC.

Systematic analyses of the role of prognostic and immunological EIF3A, a reader protein, in clear cell renal cell carcinoma

BackgroundEukaryotic initiation factor 3a (EIF3A), a “reader” protein for RNA methylation, has been found to be involved in promoting tumorigenesis in a variety of cancers. The impact of EIF3A in clear cell renal cell carcinoma (ccRCC) has yet to be reported. This study aimed to identify the prognostic value of EIF3A in ccRCC and investigate the relationship between EIF3A expression and immune infiltration.MethodsWe collected 29 m6A-related mRNA data and clinicopathological parameters from The Cancer Genome Atlas (TCGA) database. Logistic regression analyses were used to analyse the correlation between EIF3A expression and clinical characteristics. Immunohistochemistry (IHC) was applied to examine EIF3A levels in normal and ccRCC tissues. Univariate and multivariate analyses were conducted to recognize independent factors associated with overall survival (OS) and disease-free survival (DFS). The nomogram aimed to predict the 1-, 3- and 5-year survival probabilities. Gene set enrichment analysis (GSEA) was carried out to determine the potential functions and related signalling pathways of EIF3A expression. To investigate EIF3A of coexpressed genes, we used LinkedOmics, and the results were subjected to enrichment analysis. Simultaneously, LinkedOmics and STRING datasets were used to identify EIF3A coexpressed genes that were visualized via Cytoscape. Finally, we evaluated whether EIF3A expression correlated with the infiltration of immune cells and the expression of marker genes in ccRCC by Tumour Immune Estimation Resource (TIMER) and Gene Expression Profiling Interactive Analysis (GEPIA).ResultEIF3A expression was significantly different between ccRCC tissues and normal tissues. EIF3A expression was correlated with poor prognostic clinicopathological factors, and K–M analyses revealed that low EIF3A expression was correlated with a poor prognosis. The results of univariate and multivariate analyses proved that EIF3A was a prognostic factor in ccRCC patients. GSEA results indicated that EIF3A high expression was enriched in the renal cell carcinoma pathway. EIF3A expression was significantly positively correlated with B cells, CD8 + T cells, CD4 + T cells, neutrophils, macrophages, and dendritic cells. Furthermore, EIF3A expression was associated with most marker genes of immune cells.ConclusionsEIF3A could serve as a potential biomarker for prognostic and diagnostic stratification of ccRCC and is related to immune cell infiltrates.

Machine learning-based pathomics signature could act as a novel prognostic marker for patients with clear cell renal cell carcinoma

Traditional histopathology performed by pathologists through naked eyes is insufficient for accurate survival prediction of clear cell renal cell carcinoma (ccRCC). A total of 483 whole slide images (WSIs) data from three patient cohorts were retrospectively analyzed. We performed machine learning algorithm to identify optimal digital pathological features and constructed machine learning-based pathomics signature (MLPS) for ccRCC patients. Prognostic performance of the prognostic model was also verified in two independent validation cohorts. MLPS could significantly distinguish ccRCC patients with high survival risk, with hazard ratio of 15.05, 4.49 and 1.65 in three independent cohorts, respectively. Cox regression analysis revealed that the MLPS could act as an independent prognostic factor for ccRCC patients. Integration nomogram based on MLPS, tumour stage system and tumour grade system improved the current survival prediction accuracy for ccRCC patients, with area under curve value of 89.5%, 90.0%, 88.5% and 85.9% for 1-, 3-, 5- and 10-year disease-free survival prediction. The machine learning-based pathomics signature could act as a novel prognostic marker for patients with ccRCC. Nevertheless, prospective studies with multicentric patient cohorts are still needed for further verifications.

Ferroptosis-Related Gene Signature Accurately Predicts Survival Outcomes in Patients With Clear-Cell Renal Cell Carcinoma.

As a type of regulated cell death induced by Ras selective lethal (RSL) compounds such as erasti, ferroptosis is characterized by iron-dependent lipid peroxide accumulation to lethal levels. At present, little is known about the role of ferroptosis-related genes in clear-cell renal cell carcinoma (ccRCC). In the present study, the expression data of ferroptosis-related genes in ccRCC were obtained from the Cancer Genome Atlas (TCGA), and COX regression analysis was performed to construct a risk model of ferroptosis prognostic signature. The GEO database was used to verify the accuracy of the model. The following findings were made: the results reveal that the prognostic signature constructed by 11 ferroptosis genes (CARS, CD44, DPP4, GCLC, HMGCR, HSPB1, NCOA4, SAT1, PHKG2, GOT1, HMOX1) was significantly related to the overall survival (OS) of ccRCC patients based on the lowest Akaike information criterion (AIC); multivariate analysis indicates that ferroptosis-related gene prognostic signature was an independent prognostic factor in ccRCC patients; the calibration curve and c-index value (0.77) demonstrate that the nomogram with the signature could predict the survival of ccRCC patients; and enrichment analysis shows that the high-risk group were enriched in humoral immunity and receptor interaction pathways. The aforementioned findings indicate that the ferroptosis-related gene signature can accurately predict the prognosis of ccRCC patients and provide valuable insights for individualized treatment.

Expression and prognostic significance of fatty acid synthase in clear cell renal cell carcinoma

Fatty acid synthase (FASN), a key enzyme essential for fatty acid (FA) synthesis, was reportedly implicated in the initiation and progression of various cancers. However, the clinical significance of FASN in renal cell carcinoma (RCC) has not been fully elucidated yet. Here we compare the expression profile and evaluate the prognostic significance of FASN in clear cell RCC (ccRCC) patients. FASN expression was examined in 3 pairs ccRCC and their adjacent nontumor tissues by western blotting (WB) analysis, and its expression was assessed in 145 ccRCC and 13 nontumor tissues by immunohistochemistry (IHC) analysis with tissue microarrays (TMAs). The prognosis of FASN was further investigated in large-scale database using LinkedOmics (n = 537) and The Cancer Protein Atlas (TCPA, n = 445), respectively. WB detected higher FASN expression in ccRCC than normal tissues, then IHC analysis revealed that FASN expression was positively associated with histological grade, pathological stage, tumor size and metastasis status, and negatively associated with cancer-specific survival (CSS). Univariate survival analysis demonstrated that high grade, advanced stage, large tumor, metastasis, and high FASN expression were significantly associated with a shorter CSS, and multivariate analysis revealed tumor grade, stage, metastasis and FASN were identified as independent predictors for CSS in patients with ccRCC. Further LinkedOmics and TCPA analyses confirmed that high FASN expression was correlated with a poorer overall survival (OS) of ccRCC. Collectively, these findings demonstrated FASN could be a poor prognostic factor in ccRCC patients, which indicated that FA synthesis might be implicated in the tumorigenesis and progression of ccRCC.

Identification of potential novel differentially-expressed genes and their role in invasion and migration in renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) remains one of the most common cancer types globally, and while it has been extensively studied, the molecular basis for its pathology remains incompletely understood. Herein, we profiled three previously published datasets (GSE66272, GSE100666, and GSE105261) in a single integrated analysis aimed at identifying disease-associated patterns of gene expression that may offer mechanistic insight into the drivers of this disease. We pooled expression data from 39 normal kidney samples and 39 kidney tumors, leading us to identify 310 differentially expressed genes (DEGs) that were linked to kidney cancer in all three analyzed datasets. Of these genes, 133 and 177 were up- and down-regulated, respectively, in cancer samples. We then incorporated these DEGs into a protein-protein interaction network with the STRING and Cytoscape tools, and we were able to identify signaling pathways significantly enriched for these DEGs. The relationship between DEG expression and ccRCC patient survival was further evaluated using a Kaplan-Meier approach, leading us to identify TIMP1 as an independent prognostic factor in ccRCC patients. When TIMP1 expression was disrupted in ccRCC cell lines, this impaired their migratory and invasive capabilities. In summary, we employed an integrative bioinformatics approach to identify ccRCC-related DEGs and associated signaling pathways. Together these findings offer novel insight into the mechanistic basis for ccRCC, potentially helping to identify novel therapeutic targets for the treatment of this deadly disease.

SH3BGRL2 inhibits growth and metastasis in clear cell renal cell carcinoma via activating hippo/TEAD1-Twist1 pathway.

BackgroundClear cell renal cell carcinoma (ccRCC) is one of the most prevalent malignancies in the world, and tumor metastasis is still the main reason for disease progression. Accumulating evidence shows that SH3BGRL2 may play a key role in tumor progression and metastasis. However, the role of SH3BGRL2 in ccRCC has not been systematically investigated and remains elusive.MethodsThe clinical significance of SH3BGRL2 was evaluated by bioinformatic analysis and tissue microarray (TMA) samples. SH3BGRL2 expression was determined by RT-PCR, western blot and immunohistochemistry staining. Tumor suppressive effect of SH3BGRL2 was determined by both in vitro and in vivo studies. Western blot, chromatin immunoprecipitation assay and luciferase report assay were applied for mechanism dissection.FindingsSH3BGRL2 was crucial for epithelial-mesenchymal transition (EMT) progression and metastasis in ccRCC. Clinically, SH3BGRL2 was identified as an independent prognostic factor for ccRCC patients. Gain- and loss-of-function results suggested that SH3BGRL2 played a critical role in cell proliferation, migration and invasion. Mechanistically, we found that SH3BGRL2 acted as a tumor suppressor through Hippo/TEAD1 signaling, then TEAD1 altered Twist1 expression at the transcriptional level via directly binding to its promoter region.InterpretationOur findings established that SH3BGRL2 performed as a tumor suppressor and modulator via Hippo/TEAD1-Twist1 signaling in ccRCC, and the alteration of SH3BGRL2 could serve as a functional response biomarker of tumor progression and metastasis in ccRCC.

Prognostic value of preoperative C-reactive protein /albumin ratio in patients with clear cell renal cell carcinoma

Objective To assess the prognostic value of C-reactive protein/albumin (CRP/Alb) ratio in patients with clear cell renal cell carcinoma (ccRCC). Methods The study comprised 406 ccRCC patients undergoing nephrectomy between January 2003 and December 2012 in our hospital. There were 253 males and 153 females, aged 24-80 years, with a median age of 58 years. There were 355 cases with TNM Ⅰ stage, 38 cases with Ⅱ stage, 30 cases with Ⅲ stage, 3 cases with Ⅳ stage. There were 376 cases with tumor necrosis and 40 cases without tumor necrosis. There were 395 cases of vascular invasion, 21 cases without vessel invasion. The correlations among the pretreatment CRP/Alb ratio, clinicopathological parameters, and overall survival (OS) were evaluated. We compared the prognostic value of the CRP/Alb ratio with GPS and mGPS using the area under the curve (AUC). Results CRP/Alb ratio was associated with age at surgery (P=0.007), TNM stage (P<0.001), tumor necrosis (P<0.001) and lymphovascular invasion (P<0.001), and OS (P<0.001). The multivariate analysis confirmed that the CRP/Alb ratio independently predicted the OS of patients with ccRCC (P<0.001), the Glasgow prognostic score (GPS) (P=0.001) and modified GPS (mGPS) (P=0.019) were also independent prognostic factors. For predicting 3-year survival, the AUC values for CRP/Alb (continuous), CRP/Alb (categorical), GPS and mGPS were 0.88, 0.84, 0.85, 0.80. For predicting 5-year survival, the AUC values for CRP/Alb (continuous), CRP/Alb (categorical), GPS and mGPS were 0.80, 0.79, 0.76, 0.72. The CRP/Alb ratio was superior to GPS and mGPS in predicting the 3- or 5-year survival rate of ccRCC patients. Conclusions The CRP/Alb ratio could be an independent prognostic factor in ccRCC patients. The CRP/Alb ratio could take the place of the GPS and mGPS in terms of predicting prognosis in ccRCC. Key words: Clear cell renal cell carcinoma; C-reactive protein; Albumin; Prognosis

XRCC1 serves as a potential prognostic indicator for clear cell renal cell carcinoma and inhibits its invasion and metastasis through suppressing MMP-2 and MMP-9.

X-ray repair cross-complementing group 1 (XRCC1) is a major DNA repair gene that is responsible for fixing DNA base damage and single-strand breaks by interacting with DNA components at the damage site. This study explored the clinical significance of XRCC1 in human clear cell renal cell carcinoma (ccRCC) and further examined the mechanism of the role of XRCC1 in ccRCC. The clinical relevance of XRCC1 in ccRCC was evaluated using tissue microarrays and immunohistochemical staining of two independent human ccRCC cohorts. Our data demonstrated that XRCC1 expression was dramatically decreased in ccRCC tissues compared with that in normal renal tissues and paired adjacent non-tumor tissues. Low XRCC1 expression was significantly correlated with lymph node metastasis and with worse overall and disease-specific survival in patients, as determined by log-rank tests. However, Cox regression analysis revealed that XRCC1 expression was not an independent prognostic factor in ccRCC patients. Furthermore, XRCC1 suppressed ccRCC migration and invasion by inhibiting MMP-2 and MMP-9 expression through the regulation of TIMP-2 and TIMP-1. These findings indicated that decreased XRCC1 expression was associated with lymph node metastasis but was not an independent prognostic factor in ccRCC patients. XRCC1 may serve as a potential therapeutic target for inhibiting ccRCC metastasis but cannot be used as an independent prognostic factor.

Long noncoding RNA MRCCAT1 promotes metastasis of clear cell renal cell carcinoma via inhibiting NPR3 and activating p38-MAPK signaling

BackgroundRecent evidences showed that long noncoding RNAs (lncRNAs) are frequently dysregulated and play important roles in various cancers. Clear cell renal cell carcinoma (ccRCC) is one of the leading cause of cancer-related death, largely due to the metastasis of ccRCC. However, the clinical significances and roles of lncRNAs in metastatic ccRCC are still unknown.MethodslncRNA expression microarray analysis was performed to search the dysregulated lncRNA in metastatic ccRCC. quantitative real-time PCR was performed to measure the expression of lncRNAs in human ccRCC samples. Gain-of-function and loss-of-function experiments were performed to investigate the biological roles of lncRNAs on ccRCC cell proliferation, migration, invasion and in vivo metastasis. RNA pull-down, RNA immunoprecipitation, chromatin immunoprecipitation, and western blot were performed to explore the molecular mechanisms underlying the functions of lncRNAs.ResultsThe microarray analysis identified a novel lncRNA termed metastatic renal cell carcinoma-associated transcript 1 (MRCCAT1), which is highly expressed in metastatic ccRCC tissues and associated with the metastatic properties of ccRCC. Multivariate Cox regression analysis revealed that MRCCAT1 is an independent prognostic factor for ccRCC patients. Overexpression of MRCCAT1 promotes ccRCC cells proliferation, migration, and invasion. Depletion of MRCCAT1 inhibites ccRCC cells proliferation, migration, and invasion in vitro, and ccRCC metastasis in vivo. Mechanistically, MRCCAT1 represses NPR3 transcription by recruiting PRC2 to NPR3 promoter, and subsequently activates p38-MAPK signaling pathway.ConclusionsMRCCAT1 is a critical lncRNA that promotes ccRCC metastasis via inhibiting NPR3 and activating p38-MAPK signaling. Our results imply that MRCCAT1 could serve as a prognostic biomarker and therapeutic target for ccRCC.

High mucin 5AC expression predicts adverse postoperative recurrence and survival of patients with clear-cell renal cell carcinoma.

BackgroundMucin 5AC (MUC5AC), as a member of secreted/gel-forming mucin family, was frequently found to be abnormally expressed in inflammation or malignant diseases. However, the clinic pathologic features and prognostic values of MUC5AC in clear-cell renal cell carcinoma (ccRCC) have not been reported up to now.MethodsMUC5AC expression was analyzed by immunohistochemistry on tissue microarrays. Kaplan-Meier survival curves, Univariate and Multivariate Cox analysis and newly-established nomogram model were performed to evaluate the prognostic value.ResultsMUC5AC expression was firstly found to be up-regulated in patients with ccRCC, positively associated with tumor size, pN stage, lymphovascular invasion, Fuhrman grade, rahbdoid differentiation, sarcomatoid features, tumor necrosis, ECOG-PS and recurrence. Furthermore, MUC5AC expression might be contributed to risk stratification of ccRCC patients with TNM stage III+IV or Fuhrman grade 3 or 4 for overall survival (OS) and recurrence-free survival (RFS) analysis, and it was demonstrated to be negatively correlated with OS and RFS of ccRCC patients. What's more, MUC5AC was identified as a potential independent adverse prognostic factor; prediction accuracy of MUC5AC-based new nomogram model was drastically improved for OS and RFS of ccRCC patients.ConclusionMUC5AC is a promising independent adverse prognostic factor for ccRCC patients, it maybe conducive to postoperative risk stratification and guide treatment in the future.

Enrichment of C5a-C5aR axis predicts poor postoperative prognosis of patients with clear cell renal cell carcinoma.

Anaphylatoxin C5a and its receptor C5aR on cancer cells constitute a vital axis to cancer progression. In this study, we measured C5aR level by immunohistochemistry in the same cohort of our previous C5a research, and C5a-C5aR axis status was determined by synthesizing C5a and C5aR data. C5aR was an adverse independent prognostic factor for ccRCC patients. Kaplan-Meier analyses revealed the unique position of both C5a and C5aR high population in postoperative survival, based on which patients were then shunted into C5a-C5aR enriched and non-enriched groups. Obviously, C5a-C5aR enriched patients significantly had a poorer overall survival (OS) and recurrence free survival (RFS) compared with non-enriched ones, and the independence of C5a-C5aR axis was verified by multivariable analyses (HR 2.118, P = 0.001 for OS, HR 1.715, P = 0.035 for RFS). Established nomograms based on our findings reflected much better predicting accuracy in contrast with most common used TNM and Fuhrman systems. Meanwhile, consistent with HR, C5a-C5aR axis in this study held its advantages over C5a and C5aR for OS prediction by c-index analyses, rather than RFS prediction.

High expression of HMGA2 predicts poor survival in patients with clear cell renal cell carcinoma.

High-mobility group AT-hook 2 (HMGA2) is involved in a wide spectrum of biological processes and is upregulated in several tumors, but its role in renal carcinoma remains unclear. The aim of this study was to examine the expression of HMGA2 and its relationship to the overall survival (OS) of patients with non-metastatic clear cell renal cell carcinoma (ccRCC) following surgery. The expression of HMGA2 was evaluated retrospectively by immunohistochemistry (IHC) in 162 patients with ccRCC who underwent nephrectomy in 2003 and 2004. An IHC analysis revealed that HMGA2 was expressed in the nuclei of tumor cells in 146 (90.1%) patients with ccRCC. The level of HMGA2 was positively correlated with tumor size, lymph node metastasis, and Fuhrman Grade. A Kaplan–Meier analysis with log-rank test found that patients with high HMGA2 expression had a poor outcome and that patients with low HMGA2 expression had better survival. Cox regression analysis showed that HMGA2 expression could serve as an independent prognostic factor for ccRCC patients. The efficacy of the following prognostic models was improved when HMGA2 expression was added: tumor node metastasis stage, UCLA Integrated Scoring System, Mayo Clinic stage, size, grade, and necrosis score. In summary, this study showed that HMGA2 expression is an independent prognostic factor for OS in patients with ccRCC. HMGA2 was found to be a valuable biomarker for ccRCC progression.