scholarly journals CD248+ Cancer-Associated Fibroblasts: A Novel Prognostic and Therapeutic Target for Renal Cell Carcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Chao Xu ◽  
Keying Zhang ◽  
Fa Yang ◽  
Xiang Zhou ◽  
Shaojie Liu ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Therapeutic Target ◽  
Renal Cell ◽  
Pearson Correlation ◽  
Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Cancer Associated Fibroblasts ◽  
Promoting Effect ◽  
Metabolism Regulation

BackgroundThe tumor microenvironment (TME) plays an important role in the progression of renal cell carcinoma (RCC). Cancer-associated fibroblasts (CAFs) are considered to constitute a major component of the TME and participate in various tumor-promoting molecular events. We have previously confirmed that CD248 represents a promising biomarker of CAFs, which may provide insight into CAF-based tumor-promoting effects. However, CAF-mediated tumor progression and the potential mechanism of CD248 remain largely unknown in RCC patients.MethodsExpression profiling and clinical data of RCC patients were obtained from The Cancer Genome Atlas (TCGA) database. An MCP-counter algorithm and Kaplan–Meier survival analysis were performed to explore the prognostic value of CAFs and CD248, respectively. A Pearson correlation coefficient test and Student’s t-test were employed to evaluate the relationship between immunosuppressive TME and CD248 or CAFs. Immunohistochemistry and immunofluorescence staining were performed to confirm CD248 expression within CAFs. CD248-specific siRNA was used to investigate the potential function of CD248 in CAF tumor promotion. Differentially expressed genes (DEGs), weighted gene co-expression network analysis (WGCNA), and enrichment analysis were conducted to clarify the function of CD248+ CAFs in RCC progression and the associated regulatory mechanism.ResultsCD248 overexpression and CAF infiltration could predict poor RCC prognosis, which may involve the immunosuppressive TME. CD248 may serve as a promising CAFs biomarker and be involved with the tumor-promoting effect of CAFs. Moreover, CD248+ CAF infiltration may contribute to RCC progression and an immunosuppressive TME through cell-extracellular matrix (ECM) interactions and metabolism regulation.ConclusionCD248+ CAFs participate in the regulation of RCC progression and immunosuppressive TME, which may represent a novel prognostic and therapeutic target for RCC.

scholarly journals Diagnostic and Immunotherapeutic Value of CD248 in Renal Cell Carcinoma

2020 ◽  
Author(s):  
Keying Zhang ◽  
Yao Jiang ◽  
Xiaolong Zhao ◽  
Shaojie Liu ◽  
Chao Xu ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Cox Regression ◽  
Clinical Specimen ◽  
Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Immune Checkpoints ◽  
Prognostic Signature ◽  
Cox Regression Analysis

Abstract Background: Renal cell carcinoma (RCC) is the most common malignancy in urinary system. Despite substantial improvements in available treatments, survival outcome of advanced RCC is unsatisfied. Identifying novel biomarker to assist early diagnosis and screen immunotherapy sensitive patients would be beneficial. CD248 is a promising candidate that deserves to be investigated.Methods: The Cancer Genome Atlas (TCGA) dataset and clinical specimen were adopted to analyze CD248 expression between normal and tumor tissues. Univariate and multivariate Cox regression analysis was employed to identify independent prognostic factors and construct a CD248-based prognostic signature. The correlation among present signature, tumor infiltrating immune cells, tumor mutation burden (TMB), and immunomodulatory molecules were evaluated. Weighted gene co-expression network analysis (WGCNA) and enrichment analysis was performed to explore the underlying mechanism of CD248 in RCC progression.Results: CD248 overexpressed in RCC was related with a poor prognosis, and CD248-based prognostic signature could precisely stratify RCC patients with different survival outcomes regardless of training or testing cohort. Present signature could reflect immunosuppressive landscape of RCC (i.e. increased regulatory T cells infiltration and upregulated immune checkpoints), which accompanied with deteriorated clinicopathologic indexes. TMB and immunostimulatory molecules expression also increased with the risk score generated from present signature. CD248 co-expressed gene sets were identified through WGCNA algorithm, and several immunosuppressive GO terms and KEGG pathways were significantly enriched.Conclusion: CD248 is a valuable biomarker to improve diagnostic and therapeutic efficiency of RCC. Immunosuppressive effect of CD248 co-expressed genes may provide insight for present study.

scholarly journals Clinicopathological and Preclinical Patient-Derived Model Studies Define High Expression of NRN1 as a Diagnostic and Therapeutic Target for Clear Cell Renal Cell Carcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Shuhei Kamada ◽  
Kazuhiro Ikeda ◽  
Takashi Suzuki ◽  
Wataru Sato ◽  
Sachi Kitayama ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Rna Sequencing ◽  
Therapeutic Target ◽  
Renal Cell ◽  
The Cancer Genome Atlas ◽  
Related Factor ◽  
Testicular Germ Cell ◽  
Cell Renal Cell Carcinoma ◽  
Cancer Models

BackgroundAcquired therapeutic resistance and metastasis/recurrence remain significant challenge in advance renal cell carcinoma (RCC), thus the establishment of patient-derived cancer models may provide a clue to assess the problem. We recently characterized that neuritogenesis-related protein neuritin 1 (NRN1) functions as an oncogene in testicular germ cell tumor. This study aims to elucidate the role of NRN1 in RCC.MethodsNRN1 expression in clinical RCC specimens was analyzed based on immunohistochemistry. NRN1-associated genes in RCC were screened by the RNA-sequencing dataset from The Cancer Genome Atlas (TCGA). RCC patient-derived cancer cell (RCC-PDC) spheroid cultures were established and their viabilities were evaluated under the condition of gene silencing/overexpression. The therapeutic effect of NRN1-specific siRNA was evaluated in RCC-PDC xenograft models.ResultsNRN1 immunoreactivity was positively associated with shorter overall survival in RCC patients. In TCGA RCC RNA-sequencing dataset, C-X-C chemokine receptor type 4 (CXCR4), a prognostic and stemness-related factor in RCC, is a gene whose expression is substantially correlated with NRN1 expression. Gain- and loss-of-function studies in RCC-PDC spheroid cultures revealed that NRN1 significantly promotes cell viability along with the upregulation of CXCR4. The NRN1-specific siRNA injection significantly suppressed the proliferation of RCC-PDC-derived xenograft tumors, in which CXCR4 expression is significantly repressed.ConclusionNRN1 can be a potential diagnostic and therapeutic target in RCC as analyzed by preclinical patient-derived cancer models and clinicopathological studies.

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.

scholarly journals POLR2A Drives Tumor Cell Aggressive in Both VHL and PBRM1 Mutation Renal-Cell Carcinoma

2021 ◽  
Author(s):  
Linyan Chai ◽  
Zhengguo Qiu ◽  
Xiaozhi Zhang ◽  
Rong Li ◽  
Yao Wang ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Control Group ◽  
Cell Renal Cell Carcinoma

Abstract Background: Loss of VHL always results in the loss of PBRM1 and causes aggressive clear cell renal cell carcinoma. However, VHL mutation was not significantly associated with worse survival, and PBRM1 modulate the tumor behavior is not clear. Thus, exploration of key molecules promoting the tumor aggressive is urgent in both VHL and PBRM1 RCC patient.Methods and results: POLR2A was screened out by analyzing The Cancer Genome Atlas mutation data. Gene Set Enrichment Analysis results showed that E2F, G2M, and mTOR1 pathways were all altered in response to POLR2A high expression. Furthermore, In vitro, knockdown of POLR2A in 769-P and 786-O cells resulted in cell growth arrest and cell cycle blockade compared to control cells, the mechanism though decreasing cyclin D1-CDK4 axis. In vivo results were confirmed 786-O cells in which POLR2A expression was silenced, exhibited tumor growth inhibited compared to control group.Conclusions: POLR2A was the key protein after VHL and PBRM1 mutations in RCC, inhibition of POLR2A crippled cell viability and proliferation in vivo and in vitro, We anticipate POLR2A represents a novel candidate for RCC treatment.

scholarly journals The Diagnostic and Immunotherapeutic Value of CD248 in Renal Cell Carcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Keying Zhang ◽  
Chao Xu ◽  
Shaojie Liu ◽  
Yao Jiang ◽  
Xiaolong Zhao ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Cox Regression ◽  
Treatment Options ◽  
Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Immune Checkpoints ◽  
Prognostic Signature ◽  
Data Set

Background: Renal cell carcinoma (RCC) is the most common malignancy in the urinary system. Despite substantial improvements in available treatment options, the survival outcome of advanced RCC is unsatisfactory. Identifying novel biomarkers to assist in early diagnosis and to screen patients who are sensitive to immunotherapy would be beneficial. CD248 is a promising candidate that deserves to be investigated.Methods: The Cancer Genome Atlas (TCGA) data set and clinical specimens were adopted to analyze the expression of CD248 between normal and tumor tissues. Univariate and multivariate Cox regression analyses were employed to identify independent prognostic factors and construct a CD248-based prognostic signature. The correlation among the present signature, tumor-infiltrating immune cells (TIICs), the tumor mutation burden (TMB), and immunomodulatory molecules was evaluated. The weighted gene co-expression network analysis (WGCNA), the enrichment analysis, and the miRNA correlation analysis were performed to explore the underlying mechanism of CD248 in the progression of RCC.Results: The overexpression of CD248 in RCC was related to a poor prognosis, and a CD248-based prognostic signature could precisely stratify patients with RCC with different survival outcomes regardless of the training or testing cohort. The present signature could reflect the immunosuppressive landscape of RCC (i.e., increased infiltration of regulatory T cells and upregulated immune checkpoints), accompanied by deteriorated clinicopathologic indexes. The TMB and immunostimulatory molecules expression also increased with the risk score generated from the present signature. CD248 co-expressed gene sets were identified through the WGCNA algorithm, and several immunosuppressive Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were significantly enriched. The result of CD248-correlated miRNA further emphasized the importance of CD248 in RCC.Conclusion: CD248 is a valuable biomarker to improve the diagnostic and therapeutic efficiency of RCC. The immunosuppressive effect of CD248 co-expressed genes may provide insight for the present study, and miRNA would help to reveal the mechanism of the expressive regulation of CD248.

scholarly journals Low intratumor heterogeneity correlates with increased response to PD-1 blockade in renal cell carcinoma

2020 ◽  
Vol 12 ◽  
pp. 175883592097711
Author(s):  
Xia Ran ◽  
Jinyuan Xiao ◽  
Yi Zhang ◽  
Huajing Teng ◽  
Fang Cheng ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Checkpoint Inhibitors ◽  
Simulated Data ◽  
The Cancer Genome Atlas ◽  
Intratumor Heterogeneity ◽  
Cell Renal Cell Carcinoma ◽  
Immune Activity

Background: Intratumor heterogeneity (ITH) has been shown to be inversely associated with immune infiltration in several cancers including clear cell renal cell carcinoma (ccRCC), but it remains unclear whether ITH is associated with response to immunotherapy (e.g. PD-1 blockade) in ccRCC. Methods: We quantified ITH using mutant-allele tumor heterogeneity, investigated the association of ITH with immune parameters in patients with ccRCC ( n = 336) as well as those with papillary RCC (pRCC, n = 280) from The Cancer Genome Atlas, and validations were conducted in patients with ccRCC from an independent cohort ( n = 152). The relationship between ITH and response to anti-PD-1 immunotherapy was explored in patients with metastatic ccRCC from a clinical trial of anti-PD-1 therapy ( n = 35), and validated in three equal-size simulated data sets ( n = 60) generated by random sampling with replacement based on this clinical trial cohort. Results: In ccRCC, low ITH was associated with better survival, more reductions in tumor burden, and clinical benefit of anti-PD-1 immunotherapy through modulating immune activity involving more neoantigens, elevated expression of HLA class I genes, and higher abundance of dendritic cells. Furthermore, we found that the association between the level of ITH and response to PD-1 blockade was independent of the mutation status of PBRM1 and that integrating both factors performed better than the individual predictors in predicting the benefit of anti-PD-1 immunotherapy in ccRCC patients. In pRCC, increased immune activity was also observed in low- versus high-ITH tumors, including higher neoantigen counts, increased abundance of monocytes, and decreased expression of PD-L1 and PD-L2. Conclusions: ITH may be helpful in the identification of patients who could benefit from PD-1 blockade in ccRCC, and even in pRCC where no genomic metrics has been found to correlate with response to immune checkpoint inhibitors.

scholarly journals MP72-02 METABOLISM RE-PROGRAMMING AS A THERAPEUTIC TARGET FOR DRUG RESISTANT RENAL CELL CARCINOMA

2018 ◽  
Vol 199 (4S) ◽  
Author(s):  
Hirofumi Yoshino ◽  
Kazutaka Miyamoto ◽  
Masaya Yonemori ◽  
Satoru Sugita ◽  
Takashi Sakaguchi ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Therapeutic Target ◽  
Renal Cell ◽  
Drug Resistant

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 CD248 as a bridge between angiogenesis and immunosuppression: a promising prognostic and therapeutic target for renal cell carcinoma

2021 ◽  
Vol 0 (0) ◽  
pp. 1741-1741
Author(s):  
Shaojie Liu ◽  
Chao Xu ◽  
Keying Zhang ◽  
Donghui Han ◽  
Fa Yang ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Therapeutic Target ◽  
Renal Cell

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.

Sign in / Sign up

Export Citation Format

Share Document