Prognosis Of Renal Cell Carcinoma Patients Research Articles

Comprehensive assessment of the association between tumor-infiltrating immune cells and the prognosis of renal cell carcinoma.

According to current statistics, renal cancer accounts for 3% of all cancers worldwide. Renal cell carcinoma (RCC) is the most common solid lesion in the kidney and accounts for approximately 90% of all renal malignancies. Increasing evidence has shown an association between immune infiltration in RCC and clinical outcomes. To discover possible targets for the immune system, we investigated the link between tumor-infiltrating immune cells (TIICs) and the prognosis of RCC. To investigate the effects of 22 TIICs on the prognosis of RCC patients and identify potential therapeutic targets for RCC immunotherapy. The CIBERSORT algorithm partitioned the 22 TIICs from the Cancer Genome Atlas cohort into proportions. Cox regression analysis was employed to evaluate the impact of 22 TIICs on the probability of developing RCC. A predictive model for immunological risk was developed by analyzing the statistical relationship between the subpopulations of TIICs and survival outcomes. Furthermore, multivariate Cox regression analysis was used to investigate independent factors for the prognostic prediction of RCC. A value of P < 0.05 was regarded as statistically significant. Compared to normal tissues, RCC tissues exhibited a distinct infiltration of immune cells. An immune risk score model was established and univariate Cox regression analysis revealed a significant association between four immune cell types and the survival risk connected to RCC. High-risk individuals were correlated to poorer outcomes according to the Kaplan-Meier survival curve (P = 1E-05). The immunological risk score model was demonstrated to be a dependable predictor of survival risk (area under the curve = 0.747) via the receiver operating characteristic curve. According to multivariate Cox regression analysis, the immune risk score model independently predicted RCC patients' prognosis (hazard ratio = 1.550, 95%CI: 1.342-1.791; P < 0.001). Finally, we established a nomogram that accurately and comprehensively forecast the survival of patients with RCC. TIICs play various roles in RCC prognosis. The immunological risk score is an independent predictor of poor survival in kidney cancer cases.

Clinical utility of keratin 14 expression measurement in reflecting the tumor properties and prognosis in patients with renal cell carcinoma: a study with long-term follow-up.

Keratin 14 (KRT14) is hypothesized to be involved in the pathogenesis of renal cell carcinoma (RCC) based on its tumorigenic role in various cancers and its relationship with the prognosis of other urinary system malignancies. This study aimed to evaluate the correlation of KRT14 with tumor properties and prognosis in RCC patients. Data from 180 RCC patients who received tumor resection were retrospectively reviewed. The KRT14 was assessed by immunohistochemistry (IHC) staining in tumor tissues and non-tumor tissues. KRT14 was insufficiently expressed in both tumor and non-tumor tissues, with median (interquartile range) IHC score of 2.0 (0.0-3.4) and 1.0 (0.0-2.0), respectively. While it was relatively higher in tumor versus non-tumor tissues (P < 0.001). Besides, tumor KRT14 was positively correlated with the pathological grade (P = 0.038), tumor size (P = 0.012), T stage (P = 0.006), and TNM stage (P = 0.018). Interestingly, tumor KRT14 high predicted shorter accumulating recurrence-free survival (RFS) (P = 0.003) and accumulating overall survival (OS) (P = 0.001), which was further verified by the multivariate Cox's regression analysis (both P < 0.05). Furthermore, tumor KRT14 high estimated shorter RFS and OS from the Gene Expression Profiling Interactive Analysis and Human Protein ATLAS databases (all P < 0.05). Subgroup analyses indicated that the correlation of tumor KRT14 with accumulating RFS and accumulating OS was more pronounced in RCC patients with better physical status (such as age < 65years and better eastern cooperative oncology group performance status) and higher tumor stages (such as higher pathological grade). High KRT14 in tumor tissue could reflect an advanced tumor features and unsatisfying survival in RCC patients.

CircPDSS1 accelerates malignant progression of renal cell carcinoma through sponging of miR-182-5p

Purpose: To investigate the biological function and mechanisms of circPDSS1 in triggering malignant progression of renal cell carcinoma (RCC).&#x0D; Methods: Quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to determine circPDSS1 levels in 50 pairs of RCC and para-cancerous tissues. The relationship between circPDSS1 level and pathological indices in RCC patients was analyzed, while the in vitro effect of circPDSS1 in regulating RCC proliferation was assessed using cell counting kit-8 (CCK-8), colony formation and 5- ethynyl-2’- deoxyuridine (EdU) assay. The sponge effect of circPDSS1 on miR-182-5p was examined by bioinformatics analysis and dual- luciferase reporter assay, while their involvement in mediating malignant progression of RCC was analyzed using rescue experiments. In vivo, the influence of circPDSS1 on RCC growth was determined by establishing a xenograft model in nude mice. Thereafter, RCC tissues were harvested from mice to assess relative levels of miR-182-5p and Ki-67.&#x0D; Results: CircPDSS1 was highly expressed in RCC tissues (p &lt; 0.05). A high level of circPDSS1 correlated with advanced tumor staging and low overall survival. Knockdown of circPDSS1 inhibited RCC cell proliferation, and CircPDSS1 sponged and negatively regulated miR-182-5p (p &lt; 0.05). MiR182-5p was able to abolish regulatory effect of circPDSS1 on malignant proliferative potential in RCC cells. In nude mice bearing RCC, in vivo knockdown of circPDSS1 slowed down tumor growth and decreased positive expression of Ki-67 in tumor tissues (p &lt; 0.05).&#x0D; Conclusion: CircPDSS1 predicts tumor stage and prognosis in RCC patients. It triggers malignant progression of RCC through sponging of miR-182-5p.

Brusatol enhances MEF2A expression to inhibit RCC progression through the Wnt signalling pathway in renal cell carcinoma.

Renal cell carcinoma (RCC) is the most aggressive subtype of kidney tumour with a poor prognosis and an increasing incidence rate worldwide. Brusatol, an essential active ingredient derived from Brucea javanica, exhibits potent antitumour properties. Our study aims to explore a novel treatment strategy for RCC patients. We predicted 37 molecular targets of brusatol based on the structure of brusatol, and MEF2A (Myocyte Enhancer Factor 2A) was selected as our object through bioinformatic analyses. We employed various experimental techniques, including RT-PCR, western blot, CCK8, colony formation, immunofluorescence, wound healing, flow cytometry, Transwell assays and xenograft mouse models, to investigate the impact of MEF2A on RCC. MEF2A expression was found to be reduced in patients with RCC, indicating a close correlation with MEF2A deubiquitylation. Additionally, the protective effects of brusatol on MEF2A were observed. The overexpression of MEF2A inhibits RCC cell proliferation, invasion and migration. In xenograft mice, MEF2A overexpression in RCC cells led to reduced tumour size compared to the control group. The underlying mechanism involves the inhibition of RCC cell proliferation, invasion, migration and epithelial-mesenchymal transition (EMT) through the modulation of Wnt/β-catenin signalling. Altogether, we found that MEF2A overexpression inhibits RCC progression by Wnt/β-catenin signalling, providing novel insight into diagnosis, treatment and prognosis for RCC patients.

PLCL1 suppresses tumour progression by regulating AMPK/mTOR-mediated autophagy in renal cell carcinoma.

Autophagy has been increasingly recognized as a critical regulatory mechanism in the maintenance of cellular homeostasis. A previous study showed that phospholipase C-like protein 1 (PLCL1) is associated with lipid metabolism in renal cell carcinoma (RCC). However, it is unclear whether PLCL1 regulates autophagy, thereby influencing the progression of RCC. Bioinformatics analysis of five microarray datasets revealed that expression of PLCL1 is decreased in tumours and is positively correlated with prognosis in RCC patients. Three independent public datasets, clinical RCC tissues and RCC cell lines, were validated using real-time qPCR, western blotting and immunohistochemistry. Using wound healing and transwell assays, we observed that elevated PLCL1 levels decreased the migratory distance and the invasive number of 786-O and ACHN cells, but PLCL1 knockdown reversed these changes in 769P cell lines compared to those in controls. The results of flow cytometry analysis indicated that PLCL1 promotes apoptosis. Moreover, transcriptional analysis based on stable overexpression of PLCL1 in 786-O cells revealed that PLCL1 is related to autophagy, and western blotting and autophagic experimental results further verified these findings. Mechanistic investigations confirmed that PLCL1 activates the AMPK/mTOR pathway and interacts with decidual protein induced by progesterone (DEPP). Collectively, our data suggest that PLCL1 functions as a suppressor of RCC progression by activating the AMPK/mTOR pathway, interacting with DEPP, initiating autophagy and inducing apoptosis. PLCL1 may be a promising therapeutic target for the diagnosis and treatment of ccRCC patients.

RBM47 restrains renal cell carcinoma progression and chemoresistance through interacting with lncRNA HOXB-AS1

RNA binding proteins have the critical role in renal cell carcinoma (RCC) progression. However, the role of RBM47 in RCC has not been elucidated. In this study, we found that RBM47 was downregulated in RCC tissues and its expression was negatively correlated with the prognosis of RCC patients. Also, we found that the expression of RBM47 was regulated by CBP/P300-mediated H3K27ac in RCC. Functionally, RBM47 restrained RCC cells proliferation and metastasis. Mechanistically, RBM47 interfered with the interaction between HOXB-AS1 and p53 proteins via directly binding with HOXB-AS1, finally promoted the entry of p53 into the nucleus and therefore activated the p53 signaling. Moreover, RBM47 had a synergistic anticancer effect with sunitinib both in vivo and in vitro.

Identification of immune cell infiltration profiles in renal cell carcinoma and their clinical significance.

Renal cell carcinoma (RCC) is the most common malignancy of the urinary system, accounting for 3.7% of all new malignancies. The prognosis of RCC patients is still poor, especially patients in advanced stage. Limited studies have fully clarified the role of immune cell infiltration profiles in the prognosis and immunotherapy of RCC. In current study, we evaluated the abundance of the 22 tumor-infiltrating immune cells (TIICs) with CIBERSORT methods. The correlation between TIICs and clinicopathological parameters, tumor immune dysfunction and exclusion (TIDE) score and immunophenoscore (IPS) of RCC patients were also explored. Significant correlations were obtained between TIICs subpopulation and specific clinicopathologic parameters of RCC, including age, gender, tumor grade, clinical stage, T stage and distant metastasis. Moreover, RCC patients with high level of memory activated CD4 T cells, follicular helper T cells and regulatory T cells had a worse overall survival (OS) rate. RCC patients with high level of CD 8 + T cells and M1 macrophages had a lower TIDE score and higher anti-CTLA IPS, higher anti-PD1 IPS as well as higher anti-PD1/CTLA4 IPS. Our results clarified the immune cell infiltration profiles of RCC. RCC patients with high level of CD 8 + T cell and M1 macrophages had a lower TIDE score and higher IPS, suggesting that RCC patients with high level of CD 8 + T cell and M1 macrophages may benefit from immunotherapy.

Immunotherapy and Immune Infiltration in Patients with Clear Cell Renal Cell Carcinoma: A Comprehensive Analysis.

On a global scale, renal cell carcinoma (RCC) is the second most common form of cancer and the 10th leading cause of cancer-related deaths. There are about 70% of cases of RCC that are clear cell renal cell carcinomas (ccRCCs). This study explores possible targets for immune therapy in patients with RCC. In the recent years, immunotherapy has been applied to RCC patients. In order to identify genes that are closely associated with immune cells, a weighted gene coexpression network analysis (WGCNA) was conducted. A close association was found between genes involved in MEred and M0 macrophages, M1 macrophages, and M2 macrophages. A prognostic prediction model is subsequently developed by incorporating the OS and the expression level of key genes from the RCC cohort into a univariate COX regression analysis, a multivariate COX regression analysis, and a combined COX regression analysis. We finally discovered that 6 genes are closely associated with the prognosis of RCC patients, including SLC16A12, SLC2A9, IGF2BP2, EMX2, ANK3, and METTL7A. The survival analysis proved the prognostic prediction value of the model. The 1-year, 3-year, and 5-year AUC of ROC curves are 0.759, 0.723, and 0.733, respectively. For clinical ROC curves, the AUC score for risk score, stage, grade, and T stage is 0.759, 0.824, 0722, and 0.736, respectively. The nomogram was constructed for better prognosis prediction of RCC patients. In addition, GSVA and GO enrichment analysis was performed to explore the potential pathways that are closely associated with genes involved in the prognostic prediction model. Accordingly, our study demonstrates that immune cells play a crucial role in RCC infiltration. The development of a prognostic prediction model is a potential new prognostic biomarker and potential immunotherapy target for tumors.

Prognostic value of glucose to lymphocyte ratio for patients with renal cell carcinoma undergoing laparoscopic nephrectomy: A multi-institutional, propensity score matching cohort study.

BackgroundWe evaluated the prognostic value of preoperative blood glucose to lymphocyte ratio (GLR) in renal cell carcinoma (RCC) patients who underwent laparoscopic nephrectomy through a multi-institutional clinical study.MethodsA total of 420 patients with RCC from three medical centers from 2014 to 2019 were included in this study. The effect of GLR on overall survival (OS) and cancer-specific survival (CSS) in RCC patients was assessed by Kaplan-Meier survival curves, univariate and multivariate Cox regression analysis. Moreover, a 1:1 propensity score matching (PSM) analysis of different GLR groups was utilized to further confirm the prognostic ability of GLR.ResultsThe optimal cut-off value for GLR was 6.8. Patients were divided into high GLR and low GLR groups according to the optimal cut-off value. GLR was significant association with diabetes, cardiovascular disease and AJCC stage. High GLR predicted adverse OS (P = 0.002) and CSS (P < 0.01) in RCC patients. Multivariate Cox regression analysis revealed that high GLR was an independent prognostic factor for OS [hazard ratio (HR): 2.389, 95% confidence interval (CI), 1.136–5.027, P = 0.008] and CSS (HR: 3.474, 95% CI, 1.555–7.761, P = 0.002). After PSM analysis of the patients in the high GLR and low GLR groups, high GLR still predicted poor OS (P = 0.021) and CSS (P = 0.037).ConclusionsHigh GLR is associated with adverse prognosis in RCC patients, and GLR can serve as an independent prognostic marker for OS and CSS in RCC patients receiving laparoscopic nephrectomy.

Tumor-associated macrophages promote migration and invasion via modulating IL-6/STAT3 signaling in renal cell carcinoma

Tumor-associated macrophages (TAMs) promote tumor cell growth and metastasis in various human cancers. However, the role of TAMs in renal cell carcinoma (RCC) is rarely investigated. Herein, we observed that the infiltration of TAMs was obviously elevated in RCC tumor tissues, high infiltration of TAMs was closely associated with tumor progression and poor prognosis in RCC patients. In vitro assays further indicated that the conditioned medium of TAMs (TAMs CM) facilitated migration, invasion, and epithelial-mesenchymal transition (EMT) in RCC cells. Moreover, we found that IL-6 was involved in the functions of TAMs in RCC; IL-6 neutralizing antibody (IL-6NA) partly abolished the effect of TAMs on RCC cells. In addition, we demonstrated that TAMs might exert their roles by activating STAT3 signaling in RCC, and IL-6 was responsible for TAMs-induced STAT3 signaling activation. In conclusion, our results revealed that high infiltration of TAMs may promote RCC cells migration, invasion, and EMT via modulating IL-6/STAT3 signaling, further suggesting a potential of novel treatment strategies targeting TAMs or IL-6 for metastatic RCC.

Glutathione peroxidase family and survival prognosis in patients with renal cell carcinoma.

Renal cell carcinoma (RCC) is a renal cortical tumor with high clinical incidence. The effect of glutathione peroxidases (GPXs) on RCC and the possible mechanism are still unclear. This study aims to explore the expression level of GPXs gene in RCC and its effect on the clinical prognosis of patients with RCC via bioinformatics analysis. The mRNA expressions of GPXs family genes were obtained from the public data of The Cancer Genome Atlas (TCGA) database. The Kruskal-Wails test was used to analyze the differences in mRNA expression of GPXs family genes between samples from patients with RCC and the normal population. UALAN databases were used to analyze the differences in protein expression of GPXs family genes between samples from patients with renal clear cell carcinoma and the normal population, and to evaluate the role of GPXs family genes in RCC. The Kaplan-Meier Plotter was used to analyze the correlation between different types of RCC and overall survival (OS), disease-free survival (DFS), disease-specific survival (DSS), and progression-free survival (PFS). Kaplan-Meier survival curve was drawn based on the GPX8 gene expression to study the relationship between GPX8 gene expression and prognosis of RCC patients. Based on the results of multivariate Cox regression analysis, a Nomogram scoring model for RCC prediction was established by introducing GPX8 gene. The mRNA expressions of GPX1 and GPX4 were higher in the sample of renal chromophobe cell carcinoma, renal clear cell carcinoma, and renal papillary cell carcinoma than those in the normal population (all P<0.01), and GPX7 and GPX8 were significantly over-expressed in patients with renal papillary cell carcinoma and renal clear cell carcinoma (all P<0.01). Compared with the normal group, the protein expressions of GPX1, GPX2, GPX7, and GPX8 were increased significantly in renal clear cell carcinoma (all P<0.01), while GPX3 and GPX4 expressions were decreased significantly (both P<0.01). The protein expressions of GPX1, GPX2, GPX7, and GPX8 were increased significantly in patients with renal clear cell carcinoma at different tumor grades (all P<0.01), while GPX3 and GPX4 expressions were decreased significantly (both P<0.01). Survival analysis showed that OS, DFS, DSS, and PFS were all decreased in patients with clear cell carcinoma compared with patients with papillary cell carcinoma and chromophobe cell carcinoma. According to the GPX8 level, patients were assigned into the low, medium, and high expression groups. Compared with the low GPX8 level group, the OS (P<0.01), DFS (P=0.03), DSS (P<0.01), and PFS (P=3.18×10-7) were significantly decreased in the high level group. Univariate Cox proportional regression analysis showed that the high level of GPX8 was associated with poor OS of 3 different types of renal cancer. Multifactorial analysis showed that GPX8 was an independent factor affecting the OS of patients with renal papillary cell carcinoma. Race and post tumor node metastasis (pTNM) typing were independent factors influencing the OS of patients with renal clear cell carcinoma. GPX8 and pTMN were independent factors influencing the OS of patients with renal chromophobe cell carcinoma. Based on these variables, the Nomogram risk models of 3 types of cell carcinoma were established, and the discrimination and calibration of the models were evaluated using the Consistency index (C-index) and calibration curves. The C-index of the risk model of renal papillary cell carcinoma was 0.62 (95% CI 0.51 to 1.00, P=0.03). The results of receiver operating characteristic (ROC) curve showed that the area under the curve (AUC) was 0.88. The C-index of the risk model of renal clear cell carcinoma was 0.72 (95% CI 0.52 to 1.00, P=0.03). The results of ROC curve showed that the AUC was 0.90. The C-index of the risk model of chromophobe cell carcinoma of kidney was 0.90 (95% CI 0.85 to 1.00, P<0.01). The results of ROC curve showed that the AUC was 0.59. GPXs family genes, especially GPX8, are potential markers for poor prognosis of RCC, and the occurrence and development of RCC can be predicted in clinical practice based on the expressions of GPXs family genes.

KMT2B promotes the growth of renal cell carcinoma via upregulation of SNHG12 expression and promotion of CEP55 transcription

BackgroundThis study aims to clarify the mechanistic action of long non-coding RNA (lncRNA) SNHG12 in the development of renal cell carcinoma (RCC), which may be associated with promoter methylation modification by KMT2B and the regulation of the E2F1/CEP55 axis.MethodsTCGA and GEO databases were used to predict the involvement of SNHG12 in RCC. Knockdown of SNHG12/E2F1/CEP55 was performed. Next, SNHG12 expression and other mRNAs were quantified by RT-qPCR. Subsequently, CCK-8 was used to detect cell proliferation. Wound healing assay and Transwell assay were used to detect cell migration and invasion, respectively. The in vitro angiogenesis of human umbilical vein endothelial cells (HUVECs) was explored by matrigel-based capillary-like tube formation assay. ChIP assay was used to detect H3K4me3 in SNHG12 promoter region. The binding of E2F1 to CEP55 promoter region was analyzed with ChIP and dual luciferase reporter assays. RIP assay was used to detect the binding of SNHG12 to E2F1. Finally, the effect of SNHG12 on the tumor formation and angiogenesis of RCC was assessed in nude mouse xenograft model.ResultsSNHG12 was highly expressed in RCC tissues and cells, and it was related to the poor prognosis of RCC patients. SNHG12 knockdown significantly inhibited RCC cell proliferation, migration, and invasion and HUVEC angiogenesis. KMT2B up-regulated SNHG12 expression through modifying H3K4me3 in its promoter region. In addition, SNHG12 promoted CEP55 expression by recruiting the transcription factor E2F1. Knockdown of SNHG12 blocked E2F1 recruitment and down-regulated the expression of CEP55, thereby inhibiting tumor formation and angiogenesis in nude mice.ConclusionThe evidence provided by our study highlighted the involvement of KMT2B in up-regulation of lncRNA as well as the transcription of CEP55, resulting in the promotion of angiogenesis and growth of RCC.

Immunotherapy Based on Tumor Microenvironment in Renal Cell Carcinoma

Renal cell carcinoma (RCC) is a common lethal urological cancer,the distant metastasis of which is the leading cause of death.Although targeted agents have remarkably improved the overall prognosis of RCC patients,nearly all the patients eventually acquire therapeutic resistance.With the advent of immune checkpoint inhibitors,immunotherapy based on tumor microenvironment (TME) has shown a broad scope in clinical application.The deepening understanding of TME leads to the changes of therapeutic strategies for advanced RCC,and the combination of targeted therapy and immunotherapy is exhibiting a promising prospect.Herein,we reviewed the TME characteristics,candidate predictive biomarkers,and possible targets for future development of drugs against RCC.

IL-1A is associated with postoperative survival and immune contexture in clear cell renal cell carcinoma.

Interleukin-1α (IL-1α) is thought to play a major role in renal cell carcinoma (RCC), but the specific mechanism is unclear. In this study, we explored the potential mechanism of the role of IL-1α in RCC. Two cohorts were included in this study: The Cancer Genome Atlas (TCGA) cohort (n=521) and Fudan University Shanghai Cancer Center (FUSCC) cohort (n=198). These cohorts were used for cell infiltration-related analyses. In TCGA cohort, expression of IL-1α was significantly increased in patients with RCC. High IL-1α mRNA expression and intratumoral IL-1α+ cells were correlated with poor OS, which remained significant after adjustment for confounders. Elevated IL-1α mRNA expression and increased intratumoral IL-1α+ cell infiltration were associated with less mast cell infiltration in RCC. Among the relationships between IL-1α and cytotoxic factors, IL-1α was correlated with IFN-γ, TNFSF11, and GZMA. Among the relationships between IL-1α and immunosuppressive factors, we found that IL-1α was correlated with PDCD1, CD274, CTL1A4, LAG3, and BTLA. Expression of IL-1α was significantly correlated with the prognosis of RCC patients. IL-1α may participate in the development and progression of renal cancer through interactions with immune infiltrating mast cells. Our data demonstrate that IL-1α is a prognostic factor and potential therapeutic target for RCC.

The prognostic role of lymph node dissection counts in the management of renal cell carcinoma: A large international cohort study

AbstractThe count of lymph node dissection (LND) has been confirmed as a prognostic indicator in various cancers while the correlation between LND counts and patient prognosis in renal cell carcinoma (RCC) was not fully studied. This research evaluated the link between LND counts and the prognosis of RCC patients. This study obtained RCC patients from the SEER database between 2010 and 2014. Univariate and multivariate Cox regression analyses were used to assess the predictive and prognostic value of LND. Besides, Kaplan–Meier (KM) survival analysis was used for survival analysis. Finally, 1264 patients were included in this study, which were divided into none LND groups (249), 1–3 LND groups (166), and 4 or more LND groups (549). Age, laterality, stage, M stage, and grade were statistically different among the three groups. In univariate Cox analysis, stage, M stage, T stage, and grade were significantly correlated with overall survival (OS). In multivariate Cox regression analysis, age, race, stage, T stage, and grade were used as independent prognostic factors. KM survival analysis revealed that grade, T stage, M stage, and stage were significantly correlated with OS. Subgroup analysis revealed that LND counts were not significantly associated with survival risk in subgroups with different clinical factors. The current North American population analysis revealed that age, race, stage, T stage, and grade may be used as independent prognostic factors for patients with RCC. Moreover, the increasing LND counts during surgery may not improve the tumor outcomes of RCC patients.

Prognostic and Clinicopathological Correlations of Pretreatment Prognostic Nutritional Index in Renal Cell Carcinoma: A Meta-Analysis

Introduction: Prognostic nutritional index (PNI) was indicted as a potential prognostic biomarker for cancer. However, the conclusion remains uncertain for renal cell carcinoma (RCC). This study was to confirm the association of PNI with prognosis and clinicopathological features in RCCs. Methods: The PubMed, EMBASE, Cochrane Library, CNKI, and Wan Fang databases were searched to retrieve eligible studies. Hazard ratios (HRs) and 95% confidence intervals (CIs) were pooled to assess the strength of the association. Results: Fifteen studies were included. The results showed a low pretreatment PNI level was significantly associated with poor overall survival (HR = 1.67, 95% CI: 1.45–1.92), progression-free survival (HR = 1.72, 95% CI: 1.23–2.42), cancer-specific survival (HR = 1.17, 95% CI: 1.09–1.26), disease-free survival (HR = 1.28, 95% CI: 1.09–1.26), and recurrence-free survival (HR = 2.14, 95% CI: 1.38–3.31). This prognostic role of PNI was almost not changed by subgroup analysis based on study design, HR source, RCC type, sample size, cutoff, follow-up, treatment, and country. Furthermore, low PNI was correlated with old age, large tumor size and high T stage, Fuhrman grade, lymph node, and distant metastases. Conclusion: Pretreatment PNI might be a promising indicator to beforehand predict the progression and prognosis for RCC patients.

LncRNA LINC00460 facilitates the proliferation and metastasis of renal cell carcinoma via PI3K/AKT signaling pathway.

Renal cell carcinoma (RCC) is one of the most prevalent cancers diseases in the worldwide. Long noncoding RNAs (LncRNAs) have been indicated as a mediator acted in tumorigenesis of RCC. LINC00460 has been reported to participate in many kinds of malignancies and promotes cancer progressions. However, the mechanism of LINC00460 on RCC is yet to be investigated. This study aimed to explore the potential function and regulation mechanism of LINC00460 in RCC. We analysed the LINC00460 expression and the prognosis in RCC patients using Gene Expression Profiling Interactive Analysis (GEPIA) and The Cancer Genome Atlas (TCGA) databases. LINC00460 level in normal renal cell line and RCC cell lines were examined by qRT-PCR. We study the effects of LINC00460 on proliferation, migration, invasion, apoptosis in RCC cells lines using a series of in vivo and in vitro experiments. RNA sequencing (RNA-seq) analysis was applied to searching potential LINC00460 related signal pathway in RCC. We identified the significant up-regulated expression of LINC00460 both in RCC tissues and cell. RCC patients with elevated LINC00460 expression have shorter survival. Up-expression of LINC00460 promoted cell proliferation, invasion and migration, meanwhile down-regulation of LINC00460 exerted inhibitory effect on these activities. We crucially identified that LNC00460 promotes development of RCC by influencing the PI3K/AKT pathway. Knockdown of LNC00460 decreased the phosphorylation of AKT and mTOR. The key finding of our study showed that LINC00460 functions as an oncogene in RCC pathogenesis by mediating the PI3K/AKT.

Renal cell carcinoma-derived exosomes deliver lncARSR to induce macrophage polarization and promote tumor progression via STAT3 pathway.

Tumor-derived exosomes play a pivotal role in regulating tumor progression by mediating crosstalk between tumor cells and immune cells such as macrophages within the tumor microenvironment. Macrophages can adopt two distinct polarization statuses and switch between M1 or M2 activation phenotypes in response to the different external stimuli. However, the role of tumor derived exosomes in the macrophage phenotypic switch and tumor development have not been elucidated in renal cell carcinoma (RCC). Here we found that high macrophage infiltration was associated with worse prognosis in RCC patients, therefore we propose our hypothesis that RCC derived exosomes might directly influence macrophage polarization and thus promote tumor progression. Both cell-based in vitro models and orthotopic transplantation in vivo tumor models were constructed and ELISA, flow cytometry, and macrophage functional studies were performed to investigate whether and how RCC-derived exosomes regulate macrophage polarization and tumor growth. The results found that these exosomes promote macrophage polarization, cytokine release, phagocytosis, angiogenesis, and tumor development. Further study revealed high amount of a recently discovered lncRNA called lncARSR in RCC-derived exosomes. Overexpression of lncARSR induced phenotypic and functional changes of macrophages in vitro and promoted tumor growth in vivo, while knockdown of lncARSR by siRNA disrupted the exosomes-mediated macrophage polarization. LncARSR interacts directly with miR-34/miR- 449 to increase STAT3 expression and mediate macrophage polarization in RCC cells. Together, RCC-derived exosomes facilitate the development of tumor through inducing macrophage polarization via transferring lncARSR, suggesting that RCC-derived exosomes, lncARSR and STAT3 are the potential therapeutic targets for treatment of RCC.

Methyltransferase-like 14 suppresses growth and metastasis of renal cell carcinoma by decreasing long noncoding RNA NEAT1.

Growing evidence supports that N6‐methyladenosine (m6A) modification acts as a critical regulator involved in tumorigenesis at the mRNA level. However, the role of m6A modification at the noncoding RNA level remains largely unknown. We found that methyltransferase‐like 14 (METTL14) was significantly downregulated in renal cell carcinoma (RCC) tissues (n = 580). Gain‐of‐function and loss‐of‐function experiments revealed that METTL14 attenuated the proliferation and migration ability of RCC cells in vivo and in vitro. The methylated RNA immunoprecipitation experiments identified that METTL14 decreased the expression of long noncoding RNA nuclear enriched abundant transcript 1_1 (NEAT1_1) in an m6A‐dependent manner. Mechanistically, RNA pull‐down assay and RNA immunoprecipitation identified NEAT1_1 directly bound to m6A reader YTH N6‐methyladenosine RNA binding protein 2 (YTHDF2). Notably, YTHDF2 accelerated the degradation of NEAT1_1 by selectively recognizing METTL14‐mediated m6A marks on NEAT1_1. Multivariate analysis suggested that METTL14 downregulation was associated with malignant characteristics and predicted poor prognosis in RCC patients. In conclusion, our results uncover a newly identified METTL14‐YTHDF2‐NEAT1_1 signaling axis, which facilitates RCC growth and metastasis and provides fresh insight into RCC therapy.

LncRNA GAPLINC Promotes Renal Cell Cancer Tumorigenesis by Targeting the miR-135b-5p/CSF1 Axis.

BackgroundLong noncoding RNAs (lncRNAs) are closely related to the occurrence and development of cancer. Gastric adenocarcinoma-associated, positive CD44 regulator, long intergenic noncoding RNA (GAPLINC) is a recently identified lncRNA that can actively participate in the tumorigenesis of various cancers. Here, we investigated the functional roles and mechanism of GAPLINC in renal cell carcinoma (RCC) development.MethodsDifferentially expressed lncRNAs between RCC tissues and normal kidney tissues were detected by using a microarray technique. RNA sequencing was applied to explore the mRNA expression profile changes after GAPLINC silencing. After gain- and loss-of-function approaches were implemented, the effect of GAPLINC on RCC in vitro and in vivo was assessed by cell proliferation and migration assays. Moreover, rescue experiments and luciferase reporter assays were used to study the interactions between GAPLINC, miR-135b-5p and CSF1.ResultsGAPLINC was significantly upregulated in RCC tissues and cell lines and was associated with a poor prognosis in RCC patients. Knockdown of GAPLINC repressed RCC growth in vitro and in vivo, while overexpression of GAPLINC exhibited the opposite effect. Mechanistically, we found that GAPLINC upregulates oncogene CSF1 expression by acting as a sponge of miR-135b-5p.ConclusionTaken together, our results suggest that GAPLINC is a novel prognostic marker and molecular therapeutic target for RCC.