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.

Gene set enrichment analysis and ingenuity pathway analysis of metastatic clear cell renal cell carcinoma cell line

2016 ◽  
Vol 311 (2) ◽  
pp. F424-F436 ◽  
Author(s):  
Mohammed I. Khan ◽  
Konrad J. Dębski ◽  
Michał Dabrowski ◽  
Anna M. Czarnecka ◽  
Cezary Szczylik
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Cell Line ◽  
Pathway Analysis ◽  
Renal Cell ◽  
Clear Cell ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Gene Set Enrichment ◽  
Cell Renal Cell Carcinoma

In recent years, genome-wide RNA expression analysis has become a routine tool that offers a great opportunity to study and understand the key role of genes that contribute to carcinogenesis. Various microarray platforms and statistical approaches can be used to identify genes that might serve as prognostic biomarkers and be developed as antitumor therapies in the future. Metastatic renal cell carcinoma (mRCC) is a serious, life-threatening disease, and there are few treatment options for patients. In this study, we performed one-color microarray gene expression (4×44K) analysis of the mRCC cell line Caki-1 and the healthy kidney cell line ASE-5063. A total of 1,921 genes were differentially expressed in the Caki-1 cell line (1,023 upregulated and 898 downregulated). Gene Set Enrichment Analysis (GSEA) and Ingenuity Pathway Analysis (IPA) approaches were used to analyze the differential-expression data. The objective of this research was to identify complex biological changes that occur during metastatic development using Caki-1 as a model mRCC cell line. Our data suggest that there are multiple deregulated pathways associated with metastatic clear cell renal cell carcinoma (mccRCC), including integrin-linked kinase (ILK) signaling, leukocyte extravasation signaling, IGF-I signaling, CXCR4 signaling, and phosphoinositol 3-kinase/AKT/mammalian target of rapamycin signaling. The IPA upstream analysis predicted top transcriptional regulators that are either activated or inhibited, such as estrogen receptors, TP53, KDM5B, SPDEF, and CDKN1A. The GSEA approach was used to further confirm enriched pathway data following IPA.

scholarly journals RNA Sequencing Reveals Upregulation of RUNX1-RUNX1T1 Gene Signatures in Clear Cell Renal Cell Carcinoma

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Zuquan Xiong ◽  
Hongjie Yu ◽  
Yan Ding ◽  
Chenchen Feng ◽  
Hanming Wei ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Hypoxia Inducible Factor ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Cell Renal Cell Carcinoma ◽  
Tissue Samples ◽  
Gene Set

In the past few years, therapies targeted at the von Hippel-Lindau (VHL) and hypoxia-inducible factor (HIF) pathways, such as sunitinib and sorafenib, have been developed to treat clear cell renal cell carcinoma (ccRCC). However, the majority of patients will eventually show resistance to antiangiogenesis therapies. The purpose of our study was to identify novel pathways that could be potentially used as targets for new therapies. Whole transcriptome sequencing (RNA-Seq) was conducted on eight matched tumor and adjacent normal tissue samples. A novel RUNX1-RUNX1T1 pathway was identified which was upregulated in ccRCC through gene set enrichment analysis (GSEA). We also confirmed the findings based on previously published gene expression microarray data. Our data shows that upregulated of the RUNX1-RUNX1T1 gene set maybe an important factor contributing to the etiology of ccRCC.

scholarly journals IMPA2 Downregulation Enhances mTORC1 Activity and Restrains Autophagy Initiation in Metastatic Clear Cell Renal Cell Carcinoma

2020 ◽  
Vol 9 (4) ◽  
pp. 956 ◽  
Author(s):  
Chia-Hao Kuei ◽  
Hui-Yu Lin ◽  
Hsun-Hua Lee ◽  
Che-Hsuan Lin ◽  
Jing-Quan Zheng ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Mtor Inhibitors ◽  
Gene Set Enrichment Analysis ◽  
Cellular Migration ◽  
Cell Renal Cell Carcinoma ◽  
Gene Set

Although mTOR inhibitors have been approved as first-line therapy for treating metastatic clear cell renal cell carcinoma (ccRCC), the lack of useful markers reduces their therapeutic effectiveness. The objective of this study was to estimate if inositol monophosphatase 2 (IMPA2) downregulation refers to a favorable outcome in metastatic ccRCC receiving mTOR inhibitor treatment. Gene set enrichment analysis predicted a significant activation of mTORC1 in the metastatic ccRCC with IMPA2 downregulation. Transcriptional profiling of IMPA2 and mTORC1-related gene set revealed significantly inverse correlation in ccRCC tissues. Whereas the enforced expression of exogenous IMPA2 inhibited the phosphorylation of Akt/mTORC1, artificially silencing IMPA2 led to increased phosphorylation of Akt/mTORC1 in ccRCC cells. The pharmaceutical inhibition of mTORC1 activity by rapamycin reinforced autophagy initiation but suppressed the cellular migration and lung metastatic abilities of IMPA2-silenced ccRCC cells. In contrast, blocking autophagosome formation with 3-methyladenine rescued the mitigated metastatic potential in vitro and in vivo in IMPA2-overexpressing ccRCC cells. Our findings indicated that IMPA2 downregulation negatively activates mTORC1 activity and could be a biomarker for guiding the use of mTOR inhibitors or autophagy inducers to combat metastatic ccRCC in the clinic.

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.

IDENTIFICATION OF DEREGULATED PATHWAYS IN METASTATIC RENAL CELL CARCINOMA USING GENE SET ENRICHMENT ANALYSIS (GSEA)

2009 ◽  
Vol 181 (4S) ◽  
pp. 37-37
Author(s):  
Alexander Buchner ◽  
Mirna Castro ◽  
Anja Hennig ◽  
Gerald Assmann ◽  
Christian G. Stief ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Gene Set Enrichment ◽  
Gene Set

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 A novel five-zinc finger-related-gene signature related to tumor immune microenvironment allows for treatment stratification and predicts prognosis in clear cell renal cell carcinoma patients

2021 ◽  
Author(s):  
Feilong Zhang ◽  
Jiyue Wu ◽  
Jiandong Zhang ◽  
Peng Cao ◽  
Zejia Sun ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Zinc Finger ◽  
Renal Cell ◽  
Drug Sensitivity ◽  
Cox Regression ◽  
Clear Cell ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Cell Renal Cell Carcinoma

Abstract Background Clear cell renal cell carcinoma (ccRCC) is one of the most prevalent renal malignant tumors, which survival rate and quality of life of ccRCC patients are not satisfactory. Therefore, identification of prognostic biomarkers of ccRCC patients will contribute to early and accurate clinical intervention and treatment, and then improve their prognosis. Methods We downloaded the original expression data of mRNAs from The Cancer Genome Atlas database and the zinc finger(ZNF)-related genes (ZRGs) from UniProt online database. Differentially expressed ZRGs (DE-ZRGs) was screened from tumor and adjacent nontumor tissues and functional enrichment analysis was conducted out. A five-ZRG signature were constructed by univariate Cox regression, least absolute shrinkage and selection operator and multivariate Cox regression. Furthermore, we screened out independent prognosis-related factors to build a nomogram by univariate and multivariate Cox regression. Potential biological pathways of five ZRGs were analyzed by Gene Set Enrichment Analysis (GSEA). Then, we further quantitatively analyze immune infiltration and evaluate tumor microenvironment by single sample GSEA. Finally, drug sensitivity of ccRCC patients was analyzed by the Genomics of Drug Sensitivity in Cancer database. Results TRIM59, VAV3, ZNF189, AGAP9 and PYGO1 were screened to be significantly associated with the prognosis of ccRCC patients. Through incorporated risk score and clinical parameters, we constructed a nomogram, which showed a good prognostic performance for ccRCC patients.

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