Systematic exploration of prognostic alternative splicing events related to immune microenvironment of Clear Cell Renal Cell Carcinoma

2021 ◽  
Author(s):  
Youyuan Deng ◽  
Jianguo Wang ◽  
Yanrui Pang ◽  
Jingyong Li ◽  
Huaixiao Zhang ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Alternative Splicing ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Functional Enrichment ◽  
Immune Microenvironment ◽  
Cell Renal Cell Carcinoma ◽  
Systematic Exploration ◽  
Immune Score

Abstract Background Clear cell renal cell carcinoma (ccRCC) accounts for almost 75% of all renal cancers, with high heterogeneity and poor prognosis. There is increasing evidence that alternative splicing (AS) is associated with tumorigenesis and immune microenvironment. However, studies on the relationship between AS events and immunity in ccRCC are still few but needed. Methods The transcriptional data and clinicopathological information of ccRCC patients were downloaded from The Cancer Genome Atlas (TCGA) database. We grouped patients according to the ESTIMATE algorithm and identified for differentially expressed AS events (DEASs). The functional enrichment analysis and unsupervised consensus analysis were performed to investigate the association between AS events and immune features. The regulatory network of survival-related AS events and intersection SFs was used to explore potential mechanisms. Results In total, 515 ccRCC patients were included in the present study. The low immune-score group had longer overall survival (OS) than the high low immune-score group. 861 AS events were identified as DEASs, and they were enriched in immune-related pathways. Unsupervised clustering analysis revealed that AS-based clusters significantly corelated with prognosis and immune features of ccRCC. Finally, MBNL1 was identified as a hub SF, and it was shown to inhibit proliferation and metastasis, promote apoptosis, and block cells in G2/M phase in 786O and A498 cells. Conclusion The present systematic exploration elaborated that not only some critical AS events were related to prognosis and immune microenvironment of ccRCC, but also the hub SF, such as MBNL1, could affect the development and progression of ccRCC.

scholarly journals Identification for prognostic value of differentially expressed genes in immune microenvironment of clear cell renal cell carcinoma

2019 ◽  
Author(s):  
Xingming Zhang ◽  
Xiaoxue Yin ◽  
Zhenhua Liu ◽  
Guangxi Sun ◽  
Xudong Zhu ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
T Cells ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Functional Enrichment ◽  
Clinicopathological Parameters ◽  
Resting Cells ◽  
Immune Microenvironment ◽  
Cell Renal Cell Carcinoma

Abstract Background: Genes related to Anchorimmune microenvironment of clear cell renal cell carcinoma (ccRCC) remains unclear. We aimed to identify related to immune microenvironment and to screen the most significant genes to predict outcomes of ccRCC. Methods: Gene expression and clinicopathological data from TCGA data portal were obtained (KIRC). Immune and stromal scores were calculated based on ESTIMATE algorithm. DEGs between low and high groups of immune scores were identified. Subsequent functional enrichment analysis and protein-protein interaction of DEGs were conducted by DAVID database. Results: Patients were divided into low and high groups by medians according to immune (median: 1038.45) and stromal scores (median: 667.945), respectively. Immune scores were significantly correlated with clinicopathological parameters and overall survival (OS). Based on immune scores, 1433 genes were up-regulated, and among them, 890 DEGs were significantly associated with OS. Based on top 10 DEGs, cases with number of up-regulated genes ≥5 were associated poor OS (P = 0.002). In addition, the mean differences of percentages of CD8 T cells (11.32%), CD4 memory resting T cells (-4.52%) and mast resting cells (-3.55%) between low and high immune scores were the most significant. Conclusions: A list of immune microenvironment-related genes in ccRCC was initially identified, and high immune score was an independent poor prognostic factor of OS. Furthermore, the combination of these genes might use to predict the efficacy of immunotherapy. Further analyses of these genes were warrant to explore their potential association with the prognosis of ccRCC.

The impact of TNFSF14 on prognosis and immune microenvironment in clear cell renal cell carcinoma

2020 ◽  
Vol 42 (9) ◽  
pp. 1055-1066
Author(s):  
Fangshi Xu ◽  
Yibing Guan ◽  
Peng Zhang ◽  
Li Xue ◽  
Xiaojie Yang ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Immune Microenvironment ◽  
Cell Renal Cell Carcinoma ◽  
The Impact

scholarly journals Prognostic implications of Aquaporin 9 expression in clear cell renal cell carcinoma

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Wen-Hao Xu ◽  
Shen-Nan Shi ◽  
Yue Xu ◽  
Jun Wang ◽  
Hong-Kai Wang ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Prognostic Value ◽  
Clear Cell ◽  
Roc Curves ◽  
Functional Enrichment ◽  
Clinicopathological Parameters ◽  
Cell Renal Cell Carcinoma ◽  
Aquaporin 9

Abstract Background Growing evidence has demonstrated immune reactivity as a confirmed important carcinogenesis and therapy efficacy for clear cell renal cell carcinoma (ccRCC). Aquaporin 9 (AQP9) is involved in many immune-related signals; however, its role in ccRCC remains to be elucidated. This study investigated AQP9 expression in tumor tissues and defined the prognostic value in ccRCC patients. Methods A total of 913 ccRCC patients with available RNA-sequence data from the Cancer Genome Atlas (TCGA) database and Fudan University Shanghai Cancer Center (FUSCC) were consecutively recruited in analyses. Differential transcriptional and proteome expression profiles were obtained and validated using multiple datasets. A partial likelihood test from Cox regression analysis was developed to address the influence of independent factors on progression-free survival (PFS) and overall survival (OS). The Kaplan–Meier method and log-rank test were performed to assess survival. Receiver operating characteristic (ROC) curves were used to describe binary classifier value of AQP9 using area under the curve (AUC) score. Functional enrichment analyses and immune infiltration analysis were used to describe significantly involved hallmark pathways of hub genes. Results Significantly elevated transcriptional and proteomic AQP9 expressions were found in ccRCC samples. Increased AQP9 mRNA expression was significantly associated with advanced clinicopathological parameters and correlated with shorter PFS and OS in TCGA and FUSCC cohorts (p < 0.001). ROC curves suggested the significant diagnostic and prognostic ability of AQP9 (PFS, AUC = 0.823; OS, AUC = 0.828). Functional annotations indicated that AQP9 is involved in the most significant hallmarks including complement, coagulation, IL6/JAK–STAT3, inflammatory response and TNF-alpha signaling pathways. Conclusion Our study revealed that elevated AQP9 expression was significantly correlated with aggressive progression, poor survival and immune infiltrations in ccRCC patients, and we validated its prognostic value in a real-world cohort. These data suggest that AQP9 may act as an oncogene and a promising prognostic marker in ccRCC.

scholarly journals A Novel Immune-Related lncRNA-Based Model for Survival Prediction in Clear Cell Renal Cell Carcinoma

2021 ◽  
Vol 2021 ◽  
pp. 1-37
Author(s):  
Zedan Zhang ◽  
Yanlin Tang ◽  
Yanjun Liu ◽  
Hongkai Zhuang ◽  
Enyu Lin ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
T Cells ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Cox Regression ◽  
Clear Cell ◽  
Functional Enrichment ◽  
Clinical Parameters ◽  
Training Set ◽  
Cell Renal Cell Carcinoma

Background. Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer whose incidence and mortality rate are increasing. Identifying immune-related lncRNAs and constructing a model would probably provide new insights into biomarkers and immunotherapy for ccRCC and aid in the prognosis prediction. Methods. The transcription profile and clinical information were obtained from The Cancer Genome Atlas (TCGA). Immune-related gene sets and transcription factor genes were downloaded from GSEA website and Cistrome database, respectively. Tumor samples were divided into the training set and the testing set. Immune-related differentially expressed lncRNAs (IDElncRNAs) were identified from the whole set. Univariate Cox regression, LASSO, and stepwise multivariate Cox regression were performed to screen out ideal prognostic IDElncRNAs (PIDElncRNAs) from the training set and develop a multi-lncRNA signature. Results. Consequently, AC012236.1, AC078778.1, AC078950.1, AC087318.1, and AC092535.4 were screened to be significantly related to the prognosis of ccRCC patients, which were used to establish the five-lncRNA signature. Its wide diagnostic capacity was revealed in different subgroups of clinical parameters. Then AJCC-stage, Fuhrman-grade, pharmaceutical, age, and risk score regarded as independent prognostic factors were integrated to construct a nomogram, whose good performance in predicting 3-, 5-, and 7-year overall survival of ccRCC patients was revealed by time-dependent ROC curves and verified by the testing sets and ICGC dataset. The calibration plots showed great agreement of the nomogram between predicted and observed outcomes. Functional enrichment analysis showed the signature and each lncRNA were mainly enriched in pathways associated with regulation of immune response. Several kinds of tumor-infiltrating immune cells like regulatory T cells, T follicular helper cells, CD8+ T cells, resting mast cells, and naïve B cells were significantly correlated with the signature. Conclusion. Therefore, we constructed a five-lncRNA model integrating clinical parameters to help predict the prognosis of ccRCC patients. The five immune-related lncRNAs could potentially be therapeutic targets for immunotherapy in ccRCC in the future.

scholarly journals Genomic Instability Promotes the Progression of Clear Cell Renal Cell Carcinoma Through Influencing the Immune Microenvironment

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiyi Wei ◽  
Yichun Wang ◽  
Chengjian Ji ◽  
Jiaocheng Luan ◽  
Liangyu Yao ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Tumor Progression ◽  
Cell Carcinoma ◽  
Genomic Instability ◽  
Renal Cell ◽  
Clear Cell ◽  
Immune Microenvironment ◽  
Cell Renal Cell Carcinoma ◽  
Low Expression

Background: Long non-coding RNAs (lncRNAs) are now under discussion as novel promising biomarkers for clear cell renal cell carcinoma (ccRCC). However, the role of genomic instability-associated lncRNA signatures in tumors has not been thoroughly uncovered. The purpose of our study is to probe the role of genomic instability-derived lncRNA signature (GILncSig) and to further investigate the mechanism of genomic instability-mediated ccRCC progression.Methods: The transcriptome data and somatic mutation profiles of ccRCC as well as clinical characteristics used in this study were obtained from The Cancer Genome Atlas database and Gene Expression Omnibus database. Lasso regression analysis was performed to construct the GILncSig. Gene set enrichment analysis (GSEA) was performed to elucidate the biological functions and relative pathways. CIBERSORT and EPIC algorithm were applied to calculate the proportion of immune cells in ccRCC. ESTIMATE algorithm was utilized to compute the immune microenvironment scores.Results: In total, 148 novel genomic instability-derived lncRNAs in ccRCC were identified. Immediately, on the basis of univariate cox analysis and lasso analysis, a GILncSig was appraised, through which the patients were allocated into High-Risk and Low-Risk groups with significantly different characteristics and prognoses. In addition, we confirmed that the somatic mutation count, tumor mutation burden, and the expression of UBQLN4, which were ascertainably associated with genomic instability, were significantly correlated with the GILncSig, indicating its reliability as a measurement of the genomic instability. Furthermore, the efficiency of GILncSig in prognostic aspects was better than the single mutation gene in ccRCC. In addition, MNX1-AS1 was defined to be a potential biomarker characterized by strong correlation with clinical features. Moreover, GSEA results indicated that the IL6/JAK/STAT3/SIGNALING pathway could be considered as a potential mechanism of genomic instability to influence tumor progression. Besides, the immune microenvironment showed significant differences between the GS-like group and the GU-like group, which was specifically manifested as high expression of CTLA4, GITR, TNFSF14, and regulatory T cells (Tregs) as well as low expression of endothelial cells (ECs) in the GU-like group. Finally, the prognostic value and clinical relevance of GILncSig were verified in GEO datasets and other urinary tumors in TCGA dataset.Conclusion: In conclusion, our study provided a new perspective for the role of lncRNAs in genomic instability and revealed that genomic instability may mediate tumor progression by affecting immunity. Besides, MNX1-AS1 played critical roles in promoting the progression of ccRCC, which may be a potential therapeutic target. What is more, the immune atlas of genomic instability was characterized by high expression of CTLA4, GITR, TNFSF14, and Tregs, and low expression of ECs.

scholarly journals Acyl-CoA Thioesterase 8 and 11 as Novel Biomarkers for Clear Cell Renal Cell Carcinoma

2020 ◽  
Vol 11 ◽  
Author(s):  
Chao-Liang Xu ◽  
Lei Chen ◽  
Deng Li ◽  
Fei-Teng Chen ◽  
Ming-Lei Sha ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Correlation Analysis ◽  
Cell Carcinoma ◽  
Cell Lines ◽  
Renal Cell ◽  
Clear Cell ◽  
Functional Enrichment ◽  
Clinical Samples ◽  
Cell Renal Cell Carcinoma ◽  
Ccrcc Cell

BackgroundClear cell renal cell carcinoma (ccRCC) is essentially a metabolic disorder characterized by reprogramming of several metabolic pathways. Acyl-coenzyme A thioesterases (ACOTs) are critical enzymes involved in fatty acid metabolism; however, the roles of ACOTs in ccRCC remain unclear. This study explored ACOTs expressions and their diagnostic and prognostic values in ccRCC.MethodsThree online ccRCC datasets from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) were utilized to measure the expressions of ACOTs in paired normal and tumor tissues. Receiver operating characteristic (ROC) curves were depicted to assess the diagnostic values of ACOTs in ccRCC. Quantitative real-time PCR and immunohistochemical analysis were performed to validate the ACOT11 expression in ccRCC cell lines and clinical samples. Survival curves and Cox regression analysis were used to evaluate the predictive values of ACOTs in clinical outcome of ccRCC patients. Functional enrichment analyses and correlation analysis were carried out to predict the potential roles of ACOT8 in tumorigenesis and progression of ccRCC.ResultsACOT1/2/8/11/13 were found to be significantly downregulated in ccRCC samples. In particular, ACOT11 was decreased in almost every matched normal-tumor pair, and had extremely high diagnostic value as shown by ROC curve analysis (AUC = 0.964). The expression of ACOT11 was further verified in ccRCC cell lines and clinical samples at mRNA and protein levels. Furthermore, clinical correlation analysis and survival analysis indicated that ACOT8 was correlated with disease progression and was an independent predictor of unfavorable outcome in ccRCC. Moreover, functional analyses suggested potential roles of ACOT8 in the regulation of oxidative phosphorylation (OXPHOS), and correlation analysis revealed an association between ACOT8 and ferroptosis-related genes in ccRCC.ConclusionOur study revealed that ACOT11 and ACOT8 are promising biomarkers for diagnosis and prognosis of ccRCC, respectively, and ACOT8 may affect ccRCC development and progression through the regulation of OXPHOS and ferroptosis. These findings may provide new strategies for precise diagnosis and personalized therapy of ccRCC.

scholarly journals Comprehensive Analysis of Regulatory Network for LINC00472 in Clear Cell Renal Cell Carcinoma

2021 ◽  
Vol 2021 ◽  
pp. 1-20
Author(s):  
Shuoze Gao ◽  
Zhiping Wang
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Noncoding Rna ◽  
Clear Cell ◽  
Functional Enrichment ◽  
Kidney Tumors ◽  
Cell Renal Cell Carcinoma ◽  
Cell Functions ◽  
Low Expression

Renal cell carcinoma (RCC) accounts for about 2% to 3% of adult malignancies, and clear cell renal cell carcinoma (ccRCC) is the most common and aggressive type of kidney cancer. It accounts for 75% of all kidney tumors. Although new targeted drugs continue to appear, they are still not suitable for all patients. Therefore, an in-depth study of the molecular mechanism of the development of ccRCC and exploration of new targets for the treatment of ccRCC will help to achieve precise treatment for ccRCC. With the development of molecular research, the study of long noncoding RNA (LncRNA) has given us a new understanding of tumors. Although LncRNA does not encode proteins, it directly interacts with proteins in various signaling pathways and affects cell functions. Therefore, it is of great significance to study the mechanism of LncRNA in ccRCC. The expression level of Linc00472 in ccRCC tissues is significantly lower than adjacent normal tissues, and its low expression is closely related to Furman’s high grade. The low expression of Linc00472 is associated with poor prognosis in patients with ccRCC. The results of protein interaction and functional enrichment analysis indicate that genes upregulated in renal clear cell carcinoma may play a major role. Analysis of target gene prediction results showed that Linc00472 may be used as ceRNA in the miR-24-3p-HLA-DPB1 pathway, miR-24-3p-CXCL9 pathway, miR-221-3p-C3aR1-VEGFR2 pathway, miR-17-5p-HLA-DQA1/HLA-DQB1 pathway, and miR-17-5p-C3aR1/C5aR1-VEGFR2 pathway which play important functions. In addition, the regulatory relationship between miR-24-3p and TNFR2 (TNFRSF1B), CD36, and COL4A1 should also be noted. The value of Linc00472 in the diagnosis and treatment of ccRCC is worthy of further study.

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