scholarly journals NDUFA4L2 is associated with clear cell renal cell carcinoma malignancy and is regulated by ELK1

PeerJ ◽  
2017 ◽  
Vol 5 ◽  
pp. e4065 ◽  
Author(s):  
Lei Wang ◽  
Zhiqiang Peng ◽  
Kaizhen Wang ◽  
Yijun Qi ◽  
Ying Yang ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Proliferation ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Expression Level ◽  
Clinical Samples ◽  
Cell Renal Cell Carcinoma

Background Clear cell renal cell carcinoma (ccRCC) is the most common and lethal cancer of the adult kidney. However, its pathogenesis has not been fully understood till now, which hinders the therapeutic development of ccRCC. NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 4-like 2 (NDUFA4L2) was found to be upregulated and play an important role in ccRCC. We aimed to further investigate the underlying mechanisms by which NDUFA4L2 exerted function and its expression level was upregulated. Methods The Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) data were mined to verify the change of NDUFA4L2 expression level in ccRCC tissues. The correlation between expression level of NDUFA4L2 and cell proliferation/apoptosis was explored by Gene Set Enrichment Analysis (GSEA). Protein-protein interaction (PPI) network of NDUFA4L2 was constructed. Biological process and involved pathways of NDUFA4L2 were analyzed by gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. The transcription factors (TFs) which can induce the expression of NDUFA4L2 were explored in clinical samples by correlation analysis and its regulation on the expression of NDUFA4L2 was verified by knockdown experiment. Results NDUFA4L2 was verified to be overexpressed in ccRCC tissues and its expression level was increased accordingly as the American Joint Committee on Cancer (AJCC) stage progressed. A high NDUFA4L2 level predicted the poor prognosis of ccRCC patients and correlated with enhanced cell proliferation and anti-apoptosis. NDUFA4L2 may interact with 14 tumor-related proteins, participate in growth and death processes and be involved in ccRCC-related pathways, such as insulin-like growth factor 1 (IGF-1), mammalian target of Rapamycin (mTOR) and phosphoinositide 3 kinase serine/threonine protein kinase (PI3K/AKT). ETS domain-containing protein ELK1 level positively correlated with the level of NDUFA4L2 in ccRCC tissues and ELK1 could regulate the expression of NDUFA4L2 in ccRCC cells. Discussion NDUFA4L2 upregulation was associated with ccRCC malignancy. NDUFA4L2 expression was regulated by ELK1 in ccRCC cells. Our study provided potential mechanisms by which NDUFA4L2 affected ccRCC occurrence and progression.

scholarly journals Functional Assessment of Four Novel Immune-Related Biomarkers in the Pathogenesis of Clear Cell Renal Cell Carcinoma

2021 ◽  
Vol 9 ◽  
Author(s):  
Daojun Lv ◽  
Xiangkun Wu ◽  
Ming Wang ◽  
Wenzhe Chen ◽  
Shuxin Yang ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Rank Aggregation ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Hub Genes ◽  
Cell Renal Cell Carcinoma ◽  
Network Analyses

BackgroundClear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma whose pathogenesis is not well understood. We aimed at identifying novel immune-related biomarkers that could be valuable in the diagnosis and prognosis of ccRCC.MethodsThe Robust Rank Aggregation (RRA) method was used to integrate differently expressed genes (DEGs) of 7 Gene Expression Omnibus (GEO) datasets and obtain robust DEGs. Weighted gene co-expression network analyses (WGCNA) were performed to identify hub genes associated with clinical traits in The Cancer Genome Atlas (TCGA) database. Comprehensive bioinformatic analyses were used to explore the role of hub genes in ccRCC.ResultsFour hub genes IFI16, LMNB1, RHBDF2 and TACC3 were screened by the RRA method and WGCNA. These genes were found to be up-regulated in ccRCC, an upregulation that could be due to their associations with late TNM stages and tumor grades. The Receiver Operating Characteristic (ROC) curve and Kaplan-Meier survival analysis showed that the four hub genes had great diagnostic and prognostic values for ccRCC, while Gene Set Enrichment Analysis (GSEA) showed that they were involved in immune signaling pathways. They were also found to be closely associated with multiple tumor-infiltrating lymphocytes and critical immune checkpoint expressions. The results of Quantitative Real-time PCR (qRT-PCR) and immunohistochemical staining (IHC) analysis were consistent with bioinformatics analysis results.ConclusionThe four hub genes were shown to have great diagnostic and prognostic values and played key roles in the tumor microenvironment of ccRCC.

scholarly journals Development and Validation of a Prognostic Gene Signature in Clear Cell Renal Cell Carcinoma

2021 ◽  
Vol 8 ◽  
Author(s):  
Chuanchuan Zhan ◽  
Zichu Wang ◽  
Chao Xu ◽  
Xiao Huang ◽  
Junzhou Su ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Overall Survival ◽  
High Risk ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Risk Scores ◽  
Cell Renal Cell Carcinoma

Clear cell renal cell carcinoma (ccRCC), one of the most common urologic cancer types, has a relatively good prognosis. However, clinical diagnoses are mostly done during the medium or late stages, when mortality and recurrence rates are quite high. Therefore, it is important to perform real-time information tracking and dynamic prognosis analysis for these patients. We downloaded the RNA-seq data and corresponding clinical information of ccRCC from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. A total of 3,238 differentially expressed genes were identified between normal and ccRCC tissues. Through a series of Weighted Gene Co-expression Network, overall survival, immunohistochemical and the least absolute shrinkage selection operator (LASSO) analyses, seven prognosis-associated genes (AURKB, FOXM1, PTTG1, TOP2A, TACC3, CCNA2, and MELK) were screened. Their risk score signature was then constructed. Survival analysis showed that high-risk scores exhibited significantly worse overall survival outcomes than low-risk patients. Accuracy of this prognostic signature was confirmed by the receiver operating characteristic curve and was further validated using another cohort. Gene set enrichment analysis showed that some cancer-associated phenotypes were significantly prevalent in the high-risk group. Overall, these findings prove that this risk model can potentially improve individualized diagnostic and therapeutic strategies.

scholarly journals Pyroptosis Regulators and Tumor Microenvironment Infiltration Characterization in Clear Cell Renal Cell Carcinoma

2022 ◽  
Vol 11 ◽  
Author(s):  
Xi Zhang ◽  
Xiyi Wei ◽  
Yichun Wang ◽  
Shuai Wang ◽  
Chengjian Ji ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Gene Set Enrichment ◽  
Cell Renal Cell Carcinoma ◽  
Gene Set

BackgroundIt is well known that chronic inflammation can promote the occurrence and progression of cancer. As a type of proinflammatory death, pyroptosis can recast a suitable microenvironment to promote tumor growth. However, the potential role of pyroptosis in clear cell renal cell carcinoma (ccRCC) remains unclear.MethodsThe transcriptome expression profile and mutation profile data of ccRCC with clinical characteristics included in this study were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Consensus clustering was used for clustering. Gene set enrichment analysis (GSEA) analysis were applied to evaluate the biological mechanisms. Single sample gene set enrichment analysis (ssGSEA) was applied for evaluating the proportion of various immune infiltrating cells. The ESTIMATE algorithm was involved to compute the immune microenvironment scores.ResultsAmong the 17 pyroptosis regulators, a total of 15 pyroptosis regulators were differential expressed between tumor and normal tissues, in which 12 of them emerged strong correlations with prognoses. According to the pyroptosis components, the ccRCC patients were divided into four pyroptosis subtypes with different clinical, molecular, and pathway characteristics. Compared with other clusters, cluster B showed the pyroptosis heat phenotype, while cluster D represented the pyroptosis cold phenotype with poor overall survival. In addition, we performed principal component analysis (PCA) on the differential genes between clusters to construct the pyroptosis index. Furthermore, the pyroptosis index was significantly correlated with survival in different tumor mutation statuses and different grades and stages. Besides, the expression of pyroptosis-related regulators was related to the infiltration of immune cells and the expression of immune checkpoints, among which AIM2 was considered as the most significant immune-related pyroptosis regulator. Ultimately, we found that AIM2 was related to the immune activation pathway and was significantly overexpressed in tumor tissues.ConclusionThis study revealed that pyroptosis regulators and pyroptosis index played an important role in the development and prognoses of ccRCC. Moreover, AIM2 can be used as a predictor of the response of immunotherapy. Assessing the pyroptosis patterns may help evaluate the tumor status and guide immunotherapy strategies.

miR-155-5p Promotes Cell Proliferation and Migration of Clear Cell Renal Cell Carcinoma by Targeting PEG3

2021 ◽  
pp. 1-10
Author(s):  
Han Wu ◽  
Haixiao Wu ◽  
Peng Sun ◽  
Desheng Zhu ◽  
Min Ma ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Proliferation ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
The Cancer Genome Atlas ◽  
Luciferase Assay ◽  
Migration And Invasion ◽  
Cell Renal Cell Carcinoma ◽  
Promote Cell Proliferation

<b><i>Objective:</i></b> miR-155-5p as an important microRNA has been extensively studied for its biological functions and mechanisms in various cancers. However, the role and underlying mechanisms in clear cell renal cell carcinoma (ccRCC) remain to be further elucidated. <b><i>Methods:</i></b> Bioinformatics methods were implemented to analyze differentially expressed genes in the cancer genome atlas database. qRT-PCR and Western blot were employed to detect the expression of miR-155-5p and paternally expressed gene 3 (PEG3) mRNA as well as protein expression. Cell lines with miR-155-5p knockdown or miR-155-5p/PEG3 co-overexpression were constructed. A series of experiments including the MTT method, wound healing assay, and transwell assay were carried out to detect the proliferation, migration, and invasion of cancer cells in different treatment groups. Bioinformatics analysis and dual-luciferase assay were conducted to confirm the targeting relationship between PEG3 and miR-155-5p in ccRCC. <b><i>Results:</i></b> miR-155-5p was found to be significantly upregulated in ccRCC cells, while PEG3 exhibited significantly low expression. The downregulation of miR-155-5p could inhibit cell proliferation, migration, and invasion of ccRCC. miR-155-5p could inhibit the expression of PEG3. The overexpression of miR-155-5p could promote cell proliferation, migration, and invasion, whereas overexpression of PEG3 could significantly attenuate such effect. Therefore, miR-155-5p may promote cell growth of ccRCC via inhibiting PEG3 expression. <b><i>Conclusion:</i></b> These findings validated the effect of miR-155-5p/PEG3 on ccRCC cells and provided novel potential targets for the prognosis and treatment of patients with ccRCC.

scholarly journals Immune Infiltration Landscape in Clear Cell Renal Cell Carcinoma Implications

2021 ◽  
Vol 10 ◽  
Author(s):  
Yongfeng Wang ◽  
Ci Yin ◽  
Lele Geng ◽  
Weiyang Cai
Keyword(s):  
Gene Expression ◽  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Activity Level ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Cell Renal Cell Carcinoma ◽  
Immune Infiltration

The malignant phenotypes of cancer are defined not only by its intrinsic tumor cells but also by the tumor infiltrating immune cells (TIICs) recruited to the cancer microenvironment. Clear cell renal cell carcinoma (ccRCC) immune microenvironment plays an important role in the tumorigenesis. This research investigated the characteristics of immune cell invasion of renal cell carcinoma and provided clues for future clinical implementation. Retrospectively, ccRCC gene expression was analyzed with appropriate clinicopathological data from the Cancer Genome Atlas (TCGA) and GEO database up to December 2019. The CIBERSORT algorithm, meta-analysis, principal component analysis (PCA), Single-Sample Gene Set Enrichment Analysis (ssGSEA) and hierarchical agglomerative clustering were used to measure and evaluate the respective proportions of 22 cell types of immune infiltration using normalized gene expression data. We also focused on evaluating the association with TIICs subpopulations and clinical features and molecular subtypes. TIICs subpopulation, especially Macrophages subgroup, T follicular helper (Tfh) cells and CD8 T cells, all contribute to tumorigenesis. Unsupervised clustering analysis revealed that there existed two distinct TIICs subgroups with different survival patterns. TIICs are extensively involved in the pathogenesis and development of the ccRCC. Characterizing the composition of TIICs influences the metabolism of tumors, activity, level, stage, and survival of patients. Collectively, the TIIC analysis has the potential to assist in the assessment and selection of ccRCC prognosis and treatment.

scholarly journals Downregulation of lncRNA ZNF582-AS1 due to DNA hypermethylation promotes clear cell renal cell carcinoma growth and metastasis by regulating the N(6)-methyladenosine modification of MT-RNR1

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Wuping Yang ◽  
Kenan Zhang ◽  
Lei Li ◽  
Yawei Xu ◽  
Kaifang Ma ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Renal Cell Carcinoma ◽  
Protein Expression ◽  
Cell Carcinoma ◽  
Clinical Significance ◽  
Renal Cell ◽  
Clear Cell ◽  
Expression Level ◽  
Cell Renal Cell Carcinoma ◽  
Qrt Pcr

Abstract Background Emerging evidence confirms that lncRNAs (long non-coding RNAs) are potential biomarkers that play vital roles in tumors. ZNF582-AS1 is a novel lncRNA that serves as a potential prognostic marker of cancers. However, the specific clinical significance and molecular mechanism of ZNF582-AS1 in ccRCC (clear cell renal cell carcinoma) are unclear. Methods Expression level and clinical significance of ZNF582-AS1 were determined by TCGA-KIRC data and qRT-PCR results of 62 ccRCCs. DNA methylation status of ZNF582-AS1 promoter was examined by MSP, MassARRAY methylation and demethylation analysis. Gain-of-function experiments were conducted to investigate the biological roles of ZNF582-AS1 in the phenotype of ccRCC. The subcellular localization of ZNF582-AS1 was detected by RNA FISH. iTRAQ, RNA pull-down and RIP-qRT-PCR were used to identify the downstream targets of ZNF582-AS1. rRNA MeRIP-seq and MeRIP-qRT-PCR were utilized to examine the N(6)-methyladenosine modification status. Western blot and immunohistochemistry assays were used to determine the protein expression level. Results ZNF582-AS1 was downregulated in ccRCC, and decreased ZNF582-AS1 expression was significantly correlated with advanced tumor stage, higher pathological stage, distant metastasis and poor prognosis. Decreased ZNF582-AS1 expression was caused by DNA methylation at the CpG islands within its promoter. ZNF582-AS1 overexpression inhibited cell proliferative, migratory and invasive ability, and increased cell apoptotic rate in vitro and in vivo. Mechanistically, we found that ZNF582-AS1 overexpression suppressed the N(6)-methyladenosine modification of MT-RNR1 by reducing rRNA adenine N(6)-methyltransferase A8K0B9 protein level, resulting in the decrease of MT-RNR1 expression, followed by the inhibition of MT-CO2 protein expression. Furthermore, MT-RNR1 overexpression reversed the decreased MT-CO2 expression and phenotype inhibition of ccRCC induced by increased ZNF582-AS1 expression. Conclusions This study demonstrates for the first time that ZNF582-AS1 functions as a tumor suppressor gene in ccRCC and ZNF582-AS1 may serve as a potential biomarker and therapeutic target of ccRCC.

scholarly journals Identification of Six Potentially Long Noncoding RNAs as Biomarkers Involved Competitive Endogenous RNA in Clear Cell Renal Cell Carcinoma

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
Kang Yang ◽  
Xiao-fan Lu ◽  
Peng-cheng Luo ◽  
Jie Zhang
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Expression Profiles ◽  
Noncoding Rnas ◽  
Long Noncoding Rnas ◽  
The Cancer Genome Atlas ◽  
Cell Renal Cell Carcinoma ◽  
Cerna Network

Background. Clear cell renal cell carcinoma (ccRCC), the most common subtype of renal cell carcinoma (RCC), usually is representative of metastatic heterogeneous neoplasm that links with poor prognosis, but the pathogenesis of ccRCC remains unclear. Currently, numerous evidences prove that long noncoding RNAs (lncRNAs) are considered as competing endogenous RNA (ceRNA) to participate in cellular processes of tumors. Therefore, to investigate the underlying mechanisms of ccRCC, the expression profiles of lncRNAs, miRNAs, and mRNAs were downloaded from the Cancer Genome Atlas (TCGA) database. A total of 1526 differentially expressed lncRNAs (DElncRNAs), 54 DEmiRNAs, and 2352 DEmRNAs were identified. To determine the connection of them, all DElncRNAs were input to the miRcode database. The results indicated that 85 DElncRNAs could connect with 9 DEmiRNAs in relation to our study. Then, databases of TargetScan and miRDB were used to search for targeted genes with reference to DEmiRNAs. The results showed that 203 out of 2352 targeted genes were identified in our TCGA set. Subsequently, ceRNA network was constructed according to Cytoscape and the targeted genes were functionally analyzed to elucidate the mechanisms of DEmRNAs. The results of survival analysis and regression analysis indicated that 6 DElncRNAs named COL18A1-AS1, WT1-AS, LINC00443, TCL6, AL356356.1, and SLC25A5-AS1 were significantly correlative with the clinical traits of ccRCC patients and could be served as predictors for ccRCC. Finally, these findings were validated by quantitative RT-PCR (qRT-PCR). Based on these discoveries, we believe that this identified ceRNA network will provide a novel perspective to elucidate ccRCC pathogenesis.

scholarly journals COL6A2/3 can serve as potential therapeutic targets and prognostic biomarkers for clear cell renal cell carcinoma

2020 ◽  
Author(s):  
Wingkeung Yiu ◽  
Can-Xuan Li ◽  
Jie Chen
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Mrna Expression ◽  
Renal Cell ◽  
Clear Cell ◽  
Therapeutic Targets ◽  
Gene Set Enrichment Analysis ◽  
Prognostic Biomarkers ◽  
Cell Renal Cell Carcinoma ◽  
Tumorigenesis And Progression

Abstract Background: Growing evidence has shown that the type VI collagen alpha chain (COL6A) family involved in the tumorigenesis and progression of diverse malignancies; however, its biological roles and potential mechanisms in clear cell renal cell carcinoma (ccRCC) remain unknown. The study was designed to explore the potential mechanisms and functions of COL6As in ccRCC.Methods: ONCOMINE and GEPIA databases were used to compare the transcriptional expression data of COL6As in ccRCC samples and normal renal samples. UALCAN database was utilized to determine the association between clinicopathological features and COL6As expression. Kaplan–Meier method was employed to determine the prognostic value of COL6As mRNA expression in ccRCC. CBioPortal database was used to investigate the genetic alterations of COL6As in ccRCC. Co-expression analyses, functional enrichment analyses, and gene set enrichment analysis (GSEA) were utilized to explore the potential action mechanisms of COL6As in ccRCC. Finally, we estimated the relationship between COL6As expression with immune cell infiltrates.Results: Upregulated transcriptional COL6A2/COL6A3 expression was observed in ccRCC specimens by comparison with noncancerous renal specimens. Patients with increased COL6A2/COL6A3 mRNA expression have a poor clinical outcome and unfavorable prognosis. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and GSEA analyses showed that COL6A2/COL6A3 might promote the tumorigenesis and progression of ccRCC by involving in several cancer-related pathways, such as axon guidance, focal adhesion, ECM receptor interaction. Besides, we found that COL6A2/COL6A3 expression was significantly associated with immune infiltration levels in ccRCC.Conclusions: COL6A2 and COL6A3 could act as candidate prognostic biomarkers and therapeutic targets in ccRCC. However, further experimental work was required to validate the conclusions.

scholarly journals A novel 10 glycolysis-related genes signature could predict overall survival for clear cell renal cell carcinoma

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Qianwei Xing ◽  
Tengyue Zeng ◽  
Shouyong Liu ◽  
Hong Cheng ◽  
Limin Ma ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Overall Survival ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Cox Regression ◽  
Clear Cell ◽  
Low Risk ◽  
The Cancer Genome Atlas ◽  
Regression Analyses ◽  
Cell Renal Cell Carcinoma

Abstract Background The role of glycolysis in tumorigenesis has received increasing attention and multiple glycolysis-related genes (GRGs) have been proven to be associated with tumor metastasis. Hence, we aimed to construct a prognostic signature based on GRGs for clear cell renal cell carcinoma (ccRCC) and to explore its relationships with immune infiltration. Methods Clinical information and RNA-sequencing data of ccRCC were obtained from The Cancer Genome Atlas (TCGA) and ArrayExpress datasets. Key GRGs were finally selected through univariate COX, LASSO and multivariate COX regression analyses. External and internal verifications were further carried out to verify our established signature. Results Finally, 10 GRGs including ANKZF1, CD44, CHST6, HS6ST2, IDUA, KIF20A, NDST3, PLOD2, VCAN, FBP1 were selected out and utilized to establish a novel signature. Compared with the low-risk group, ccRCC patients in high-risk groups showed a lower overall survival (OS) rate (P = 5.548Ee-13) and its AUCs based on our established signature were all above 0.70. Univariate/multivariate Cox regression analyses further proved that this signature could serve as an independent prognostic factor (all P < 0.05). Moreover, prognostic nomograms were also created to find out the associations between the established signature, clinical factors and OS for ccRCC in both the TCGA and ArrayExpress cohorts. All results remained consistent after external and internal verification. Besides, nine out of 21 tumor-infiltrating immune cells (TIICs) were highly related to high- and low- risk ccRCC patients stratified by our established signature. Conclusions A novel signature based on 10 prognostic GRGs was successfully established and verified externally and internally for predicting OS of ccRCC, helping clinicians better and more intuitively predict patients’ survival.

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