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  • Frontiers Media SA  (15)
  • Ye, Dingwei  (15)
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  • Frontiers Media SA  (15)
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  • 1
    Online Resource
    Online Resource
    Table_1.xlsx
    Frontiers Media SA ; 2022
    In:  Frontiers in Oncology Vol. 12 ( 2022-10-14)
    Details
    In: Frontiers in Oncology, Frontiers Media SA, Vol. 12 ( 2022-10-14)
    Abstract: Renal cancer is one of the most lethal cancers because of its atypical symptoms and metastatic potential. The metabolism of amino acids and their derivatives is essential for cancer cell survival and proliferation. Thus, the construction of the amino acid metabolism-related risk signature might enhance the accuracy of the prognostic model and shed light on the treatments of renal cancers. Methods RNA expression and clinical data were downloaded from Santa Cruz (UCSC) Xena, GEO, and ArrayExpress databases. The “DESeq2” package identified the differentially expressed genes. Univariate COX analysis selected prognostic genes related to the metabolism of amino acids. Patients were divided into two clusters using the “ConsensusClusterPlus” package, and the CIBERSORT, ESTIMATE methods were explored to assess the immune infiltrations. The LASSO regression analysis constructed a risk model which was evaluated the prediction accuracy in two independent cohorts. The genomic alterations and drug sensitivity of 18-LASSO-genes were assessed. The differentially expressed genes between two clusters were used to perform functional enrichment analysis and weighted gene co-expression network analysis (WGCNA). Furthermore, external validation of TMEM72 expression was conducted in the FUSCC cohort containing 33 ccRCC patients. Results The amino acid metabolism-related genes had significant correlations with prognosis. The patients in Cluster A demonstrated better survival, lower Treg cell proportion, higher ESTIMATE scores, and higher cuproptosis-related gene expressions. Amino acid metabolism-related genes with prognostic values were used to construct a risk model and patients in the low risk group were associated with improved outcomes. The Area Under Curve of the risk model was 0.801, 0.777, and 0.767 at the first, second, and third year respectively. The external validation cohort confirmed the stable prognostic value of the risk model. WGCNA identified four gene modules correlated with immune cell infiltrations and cuproptosis. We found that TMEM72 was downregulated in tumors by using TCGA, GEO datasets (p & lt;0.001) and the FUSCC cohort (p=0.002). Conclusion Our study firstly constructed an 18 amino acid metabolism related signature to predict the prognosis in clear cell renal cell carcinoma. We also identified four potential gene modules potentially correlated with cuproptosis and identified TMEM72 downregulation in ccRCC which deserved further studies.
    Type of Medium: Online Resource
    ISSN: 2234-943X
    URL: Article
    URL: Article
    URL: Article
    DOI: 10.3389/fonc.2022.1019949
    DOI: 10.3389/fonc.2022.1019949.s001
    DOI: 10.3389/fonc.2022.1019949.s002
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
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  • 2
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    Table7.xlsx
    Frontiers Media SA ; 2021
    In:  Frontiers in Cell and Developmental Biology Vol. 9 ( 2021-12-6)
    Details
    In: Frontiers in Cell and Developmental Biology, Frontiers Media SA, Vol. 9 ( 2021-12-6)
    Abstract: Background: The tumor microenvironment affects the occurrence and development of cancers, including clear cell renal cell carcinoma (ccRCC). However, how the immune contexture interacts with the cancer phenotype remains unclear. Methods: We identified and evaluated immunophenotyping clusters in ccRCC using machine-learning algorithms. Analyses for functional enrichment, DNA variation, immune cell distribution, association with independent clinicopathological features, and predictive responses for immune checkpoint therapies were performed and validated. Results: Three immunophenotyping clusters with gradual levels of immune infiltration were identified. The intermediate and high immune infiltration clusters (Clusters B and C) were associated with a worse prognosis for ccRCC patients. Tumors in the immune-hot Clusters B and C showed pro-tumorigenic immune infiltration, and these patients showed significantly worse survival compared with patients in the immune-cold Cluster A in the training and testing cohorts ( n = 422). In addition to distinct immune cell infiltrations of immunophenotyping, we detected significant differences in DNA variation among clusters, suggesting a high degree of genetic heterogeneity. Furthermore, expressions of multiple immune checkpoint molecules were significantly increased. Clusters B and C predicted favorable outcomes in 64 ccRCC patients receiving immune checkpoint therapies from the FUSCC cohort. In 360 ccRCC patients from the FUSCC validation cohort, Clusters B and C significantly predicted worse prognosis compared with Cluster A. After immunophenotyping of ccRCC was confirmed, significantly increased tertiary lymphatic structures, aggressive phenotype, elevated glycolysis and PD-L1 expression, higher abundance of CD8 + T cells, and TCRn cell infiltration were found in the immune-hot Clusters B and C. Conclusion: This study described immunophenotyping clusters that improved the prognostic accuracy of the immune contexture in the ccRCC microenvironment. Our discovery of the novel independent prognostic indicators in ccRCC highlights the relationship between tumor phenotype and immune microenvironment.
    Type of Medium: Online Resource
    ISSN: 2296-634X
    URL: Article
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    DOI: 10.3389/fcell.2021.785410
    DOI: 10.3389/fcell.2021.785410.s001
    DOI: 10.3389/fcell.2021.785410.s002
    DOI: 10.3389/fcell.2021.785410.s003
    DOI: 10.3389/fcell.2021.785410.s004
    DOI: 10.3389/fcell.2021.785410.s005
    DOI: 10.3389/fcell.2021.785410.s006
    DOI: 10.3389/fcell.2021.785410.s007
    DOI: 10.3389/fcell.2021.785410.s008
    DOI: 10.3389/fcell.2021.785410.s009
    DOI: 10.3389/fcell.2021.785410.s010
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2021
    detail.hit.zdb_id: 2737824-X
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  • 3
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    Table_1.csv
    Frontiers Media SA ; 2022
    In:  Frontiers in Oncology Vol. 12 ( 2022-12-5)
    Details
    In: Frontiers in Oncology, Frontiers Media SA, Vol. 12 ( 2022-12-5)
    Abstract: Increasing evidence indicates that L-dopa decarboxylase (DDC), which mediates aberrant amino acid metabolism, is significantly associated with tumor progression. However, the impacts of DDC are not elucidated clearly in clear cell renal cell carcinoma (ccRCC). This study aimed to evaluate DDC prognostic value and potential mechanisms for ccRCC patients. Methods Transcriptomic and proteomic expressions of and clinical data including 532 patients with ccRCC (The Cancer Genome Atlas RNA-seq data), 226 ccRCC samples (Gene Expression Omnibus), 101 ccRCC patients from the E-MTAB-1980 cohort, and 232 patients with ccRCC with proteogenomic data (Fudan University Shanghai Cancer Center) were downloaded and analyzed to investigate the prognostic implications of DDC expression. Cox regression analyses were implemented to explore the effect of DDC expression on the prognosis of pan-cancer. The "limma" package identified the differentially expressed genes (DEGs) between high DDC subgroups and low DDC groups. Functional enrichments were performed based DEGs between DDC subgroups. The differences of immune cell infiltrations and immune checkpoint genes between DDC subgroups were analyzed to identify potential influence on immune microenvironment. Results We found significantly decreased DDC expression in ccRCC tissues compared with normal tissues from multiple independent cohorts based on multi-omics data. We also found that DDC expression was correlated with tumor grades and stages.The following findings revealed that lower DDC expression levels significantly correlated with shorter overall survival (P & lt;0.001) of patients with ccRCC. Moreover, we found that DDC expression significantly correlated with an immunosuppressive tumor microenvironment, higher intra-tumoral heterogeneity, elevated expression of immune checkpoint CD274, and possibly mediated malignant behaviors of ccRCC cells via the PI3k/Akt signaling pathway. Conclusion The present study is the first to our knowledge to indicate that decreased DDC expression is significantly associated with poor survival and an immune-suppressive tumor microenvironment in ccRCC. These findings suggest that DDC could serve as a biomarker for guiding molecular diagnosis and facilitating the development of novel individual therapeutic strategies for patients with advanced ccRCC.
    Type of Medium: Online Resource
    ISSN: 2234-943X
    URL: Article
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    DOI: 10.3389/fonc.2022.1079446
    DOI: 10.3389/fonc.2022.1079446.s001
    DOI: 10.3389/fonc.2022.1079446.s002
    DOI: 10.3389/fonc.2022.1079446.s003
    DOI: 10.3389/fonc.2022.1079446.s004
    DOI: 10.3389/fonc.2022.1079446.s005
    DOI: 10.3389/fonc.2022.1079446.s006
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
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  • 4
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    Image_2.png
    Frontiers Media SA ; 2022
    In:  Frontiers in Immunology Vol. 13 ( 2022-8-1)
    Details
    In: Frontiers in Immunology, Frontiers Media SA, Vol. 13 ( 2022-8-1)
    Abstract: Sarcomatoid differentiation is a highly aggressive pathological characteristic of renal cell carcinoma (RCC) and is characterized by susceptibility to progression and extremely poor prognosis. In this study, we included all genomic alteration events that led to a loss of protein function of MTAP and CDKN2A, and enrolled 5,307 RCC patients with genomic sequencing data from Western and Chinese cohorts. Notably, MTAP / CDKN2A MUT occurred in the Chinese population ~2 times more frequently than in the Western cohort and showed significant co-mutation trends. We found significantly higher proportions of sarcomatoid-positive patients with MTAP MUT or CDKN2A MUT compared with MTAP / CDKN2A wild-type (WT) patients ( P   & lt; 0.001). Of the 574 RCC samples from the FUSCC cohort and 3,563 RCC samples from 17 independent cohorts, the MTAP / CDKN2A MUT significantly predicted extremely poor outcomes ( P   & lt; 0.0001). The Western cohort suggested a concordant relationship between MTAP / CDKN2A MUT and sarcomatoid differentiation in RCC. Moreover, although MTAP / CDKN2A MUT RCC may be insensitive to targeted therapy, the high degree of tumor heterogeneity and higher PD-L1 and CXCL13 expression characterizations reflected that MTAP / CDKN2A -deficient features could benefit from immunotherapy for patients with RCC. This study utilized RCC samples from large-scale, global, multicenter sequencing cohorts and first proved that MTAP / CDKN2A deficiency significantly correlates with sarcomatoid differentiation in RCC and predicts aggressive progression, poor prognosis, and primary resistance to targeted therapy and potential favorable responses to immune checkpoint blockade. Unlike conventional targeted therapies, emerging drugs such as immunotherapies or synthetic lethal PRMT5 inhibitors may become novel therapeutic options for patients with MTAP/CDKN2A MUT RCC.
    Type of Medium: Online Resource
    ISSN: 1664-3224
    URL: Article
    URL: Article
    URL: Article
    DOI: 10.3389/fimmu.2022.953721
    DOI: 10.3389/fimmu.2022.953721.s001
    DOI: 10.3389/fimmu.2022.953721.s002
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
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  • 5
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    Image2.TIF
    Frontiers Media SA ; 2021
    In:  Frontiers in Cell and Developmental Biology Vol. 9 ( 2021-12-8)
    Details
    In: Frontiers in Cell and Developmental Biology, Frontiers Media SA, Vol. 9 ( 2021-12-8)
    Abstract: The tumor microenvironment (TME) affects the biologic malignancy of clear cell renal cell carcinoma (ccRCC). The influence of the 5-methylcytosine (m 5 C) epigenetic modification on the TME is unknown. We comprehensively assessed m 5 C modification patterns of 860 ccRCC samples (training, testing, and real-world validation cohorts) based on 17 m 5 C regulators and systematically integrated the modification patterns with TME cell-infiltrating characterizations. Our results identified distinct m 5 C modification clusters with gradual levels of immune cell infiltration. The distinct m 5 C modification patterns differ in clinicopathological features, genetic heterogeneity, patient prognosis, and treatment responses of ccRCC. An elevated m 5 C score, characterized by malignant biologic processes of tumor cells and suppression of immunity response, implies an immune-desert TME phenotype and is associated with dismal prognosis of ccRCC. Activation of exhausted T cells and effective immune infiltration were observed in the low m 5 C score cluster, reflecting a noninflamed and immune-excluded TME phenotype with favorable survival and better responses to immunotherapy. Together, these findings provide insights into the regulation mechanisms of DNA m 5 C methylation modification patterns on the tumor immune microenvironment. Comprehensive assessment of tumor m 5 C modification patterns may enhance our understanding of TME cell-infiltrating characterizations and help establish precision immunotherapy strategies for individual ccRCC patients.
    Type of Medium: Online Resource
    ISSN: 2296-634X
    URL: Article
    URL: Article
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    DOI: 10.3389/fcell.2021.772436
    DOI: 10.3389/fcell.2021.772436.s001
    DOI: 10.3389/fcell.2021.772436.s002
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2021
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  • 6
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    Table_1.DOCX
    Frontiers Media SA ; 2021
    In:  Frontiers in Molecular Biosciences Vol. 7 ( 2021-1-25)
    Details
    In: Frontiers in Molecular Biosciences, Frontiers Media SA, Vol. 7 ( 2021-1-25)
    Abstract: Purpose: Lipid metabolism reprogramming is a major pathway in tumor evolution. This study investigated fatty acid synthase (FASN) mRNA expression in anthropometric adipose tissue and elucidated the prognostic value and potential mechanism of clear cell renal cell carcinoma (ccRCC). Materials and Methods: Transcription profiles were obtained from 533 ccRCC samples in The Cancer Genome Atlas (TCGA) cohorts. Real-time quantitative PCR (RT-qPCR) and immunohistochemistry were performed to detect FASN expression in 380 paired ccRCC and normal tissues from the Fudan University Shanghai Cancer Center (FUSCC). Visceral adipose tissue (VAT) and subcutaneous adipose tissue were at the level of the umbilicus as measured by magnetic resonance imaging (MRI). Non-targeted metabolomics and in vitro experiments were used to reveal the biological functions of FASN. Results: Increased FASN expression was significantly relevant to advanced T, N, and American Joint Committee on Cancer (AJCC) stages ( p & lt; 0.01) and significantly correlated to poor progression-free survival (PFS) and overall survival (OS) of 913 ccRCC patients in FUSCC and TCGA cohorts. Pearson's correlation coefficient indicated that FASN amplification was positively correlated to VAT% ( r = 0.772, p & lt; 0.001), which significantly correlated to poor PFS (HR = 2.066, p = 0.028) and OS (HR = 2.773, p = 0.023) in the FUSCC cohort. Transient inhibition or overexpression of FASN significantly regulated A498 and 786O cell proliferation and migration by regulating epithelial–mesenchymal transition. Inhibition of FASN led to a higher apoptotic rate and decreased lipid droplet formation compared with normal control in ccRCC cells. Non-targeted metabolomics showed that decreased de novo lipogenesis might be required to sustain an elevation of glycolytic activity in 786O cells by regulating galactinol, dl -lactate, N-acetylaspartylglutamate, and sucrose, thereby participating in carcinogenesis and progression of ccRCC. Conclusion: This study demonstrated that FASN expression is positively related to aggressive cell proliferation, migration, apoptosis, and lipid droplet formation and regulates metabolic disorders of the ccRCC microenvironment. Additionally, elevated FASN mRNA expression is significantly correlated to the abdominal obesity distribution, especially VAT%, which is a significant predictor of a poor prognosis for ccRCC patients.
    Type of Medium: Online Resource
    ISSN: 2296-889X
    URL: Article
    URL: Article
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    DOI: 10.3389/fmolb.2020.610229
    DOI: 10.3389/fmolb.2020.610229.s001
    DOI: 10.3389/fmolb.2020.610229.s002
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2021
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  • 7
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    DataSheet_2.pdf
    Frontiers Media SA ; 2021
    In:  Frontiers in Oncology Vol. 11 ( 2021-7-6)
    Details
    In: Frontiers in Oncology, Frontiers Media SA, Vol. 11 ( 2021-7-6)
    Abstract: This study aims to establish an N6-methyladenosine (m 6 A) RNA methylation regulators-mediated methylation model and explore its role in predicting prognostic accuracy of immune contexture and characterizations of clear cell renal cell carcinoma (ccRCC). Methods The m 6 A modification subclasses (m 6 AMS) were identified by unsupervised cluster analysis and three clusters were determined by consensus clustering algorithm in a discovering cohort. Testing and real-world validation cohorts were used to identify predictive responses for immune checkpoint therapies (ICTs) of m 6 AMS. Results Prognostic implications landscape of m 6 A regulators in cancers and its differential expression levels in ccRCC patients were identified. Based on discovering cohort, ccRCC were automatically divided into three m 6 AMS, and cluster 3 showed significant worse survival than cluster 1/2. Importantly, it was found that the immune checkpoint molecules expression was significantly elevated in cluster 3. Besides, m 6 A score Low group (cluster 1 & amp;2) have significantly elevated TIDE score compared with m 6 A score High group (cluster 3). There was conspicuous tertiary lymphoid tissue, aggressive phenotype, elevated glycolysis, expression of PD-L1, abundance of CD8 + T cells, CD4 + FOXP3 + Treg cells and TCRn immune cells infiltration in the high m 6 A score group. Interestingly, there are significantly increased patients with clinical benefit in m 6 A score High group in 368 patients receiving ICTs from testing IMvigor210 (n = 292) and validation FUSCC (n = 55) cohorts. Conclusion Our discovery highlights the relationship between tumor epigenetic heterogeneity and immune contexture. Immune-rejection cluster 3 has pro-tumorigenic immune infiltration, and shows significant clinical benefits for ccRCC patients receiving ICTs, enabling patient selection for future clinical treatment.
    Type of Medium: Online Resource
    ISSN: 2234-943X
    URL: Article
    URL: Article
    URL: Article
    DOI: 10.3389/fonc.2021.709579
    DOI: 10.3389/fonc.2021.709579.s001
    DOI: 10.3389/fonc.2021.709579.s002
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2021
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  • 8
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    Image2.TIF
    Frontiers Media SA ; 2021
    In:  Frontiers in Genetics Vol. 12 ( 2021-12-7)
    Details
    In: Frontiers in Genetics, Frontiers Media SA, Vol. 12 ( 2021-12-7)
    Abstract: Increasing evidence indicates that DNA polymerase epsilon (POLE), which mediates DNA damage repair, is significantly associated with tumor prognosis. This study aimed to analyze POLE expression in tumor samples and its prognostic value for patients with clear cell renal cell carcinoma (ccRCC). We found significantly elevated POLE expression in ccRCC tissues compared with normal tissues of multiple independent cohorts. The POLE expression levels of 523 patients with ccRCC (The Cancer Genome Atlas RNA-seq data) and 179 patients with ccRCC with immunohistochemical data (Fudan University Shanghai Cancer Center) were analyzed to investigate the prognostic implications of POLE expression. Cox regression analyses were implemented to explore the effect of POLE expression on the prognosis of pan-cancer. These findings revealed that elevated POLE expression levels significantly correlated with shorter overall survival ( p & lt; 0.001, n = 701) of patients with ccRCC. These data indicate that POLE expression may serve as a prognostic biomarker for cancers. Although POLE mutations were not significantly associated with survival benefits conferred upon patients with ccRCC, a CD4 + T cell-regulated immune microenvironment was significantly activated. Moreover, we found that POLE expression in cancers significantly correlated with an immunosuppressive tumor microenvironment, higher intratumoral heterogeneity, and expression of immune checkpoint genes PDCD1, CTLA4, and CD86, possibly mediated via the JAK/STAT and Notch signaling pathways. In conclusion, the present study is the first to our knowledge to indicate that elevated POLE expression is significantly associated with poor survival and an immune-suppressive tumor microenvironment in ccRCC. These findings suggest that POLE can serve as a biomarker for guiding molecular diagnosis and facilitating the development of novel individual therapeutic strategies for patients with advanced ccRCC.
    Type of Medium: Online Resource
    ISSN: 1664-8021
    URL: Article
    URL: Article
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    URL: Article
    DOI: 10.3389/fgene.2021.751977
    DOI: 10.3389/fgene.2021.751977.s001
    DOI: 10.3389/fgene.2021.751977.s002
    DOI: 10.3389/fgene.2021.751977.s003
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2021
    detail.hit.zdb_id: 2606823-0
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  • 9
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    Table_1.xlsx
    Frontiers Media SA ; 2021
    In:  Frontiers in Immunology Vol. 12 ( 2021-11-2)
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    In: Frontiers in Immunology, Frontiers Media SA, Vol. 12 ( 2021-11-2)
    Abstract: Interferon-gamma (IFN-γ) has a complex role in modulating the tumor microenvironment (TME) during renal cell carcinoma (RCC) development. To define the role of IFN-γ response genes in RCC progression, we characterized the differential gene expression, prognostic implications, and DNA variation profiles of selected IFN-γ response signatures, which exhibited a significant hazard ratio for the overall survival (OS) and progression-free survival (PFS) of papillary, chromophobia, and clear cell RCC (ccRCC) patients ( n  = 944). Prognostic nomograms were constructed to predict the outcomes for ccRCC patients, highlighting the prognostic implications of RANBP2-type and C3HC4-type zinc finger containing 1 (RBCK1). Interestingly, large-scale pan-cancer samples ( n  = 12,521) and three single-cell RNA datasets revealed that RBCK1 showed markedly differential expression between cancer and normal tissues and significantly correlated with tumor-infiltrating immune cells, tumor purity, and immune checkpoint molecules, such as PD-L1, CTLA-4, LAG-3, and TIGIT in pan-cancer samples. Notably, the TIDE score was significantly higher in the RBCK1 high group compared with the RBCK1 low group in both ccRCC and RCC cohorts. Besides, immunohistochemistry staining showed significantly elevated RBCK1 expression in tumors ( n  = 50) compared with kidney samples ( n  = 40) from a real-world cohort, Fudan University Shanghai Cancer Center (FUSCC, Shanghai). After RBCK1 expression was confirmed in ccRCC, we found a significantly decreased number of infiltrating CD4 + T cells, CD4 + FOXP3 + Treg cells, M1 macrophages, and CD56 bight/dim NK cells in the immune-cold RBCK1 high group. In addition to the distinct heterogeneous immune microenvironment, the increased expression of RBCK1 predicted a prominently worse prognosis than the RBCK1 low group for 232 ccRCC patients in the FUSCC proteomic cohort. Furthermore, after transfected with siRNA in human ccRCC cells, extraordinarily decreased cell proliferation, migration capacities, and prominently elevated apoptosis tumor cell proportion were found in the siRNA groups compared with the negative control group. In conclusion, this study identified IFN-γ response clusters, which might be used to improve the prognostic accuracy of immune contexture in the ccRCC microenvironment. Immune-cold RBCK1 high patients have pro-tumorigenic immune infiltration and significantly worse outcomes than RBCK1 low patients based on results from multi-omics to real-world data. Our discovery of novel independent prognostic indicators for RCC highlights the association between tumor alterations and immune phenotype.
    Type of Medium: Online Resource
    ISSN: 1664-3224
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    DOI: 10.3389/fimmu.2021.734646
    DOI: 10.3389/fimmu.2021.734646.s001
    DOI: 10.3389/fimmu.2021.734646.s002
    DOI: 10.3389/fimmu.2021.734646.s003
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    DOI: 10.3389/fimmu.2021.734646.s005
    DOI: 10.3389/fimmu.2021.734646.s006
    DOI: 10.3389/fimmu.2021.734646.s007
    DOI: 10.3389/fimmu.2021.734646.s008
    DOI: 10.3389/fimmu.2021.734646.s009
    DOI: 10.3389/fimmu.2021.734646.s010
    DOI: 10.3389/fimmu.2021.734646.s011
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2021
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  • 10
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    Data_Sheet_1.zip
    Frontiers Media SA ; 2020
    In:  Frontiers in Oncology Vol. 9 ( 2020-1-10)
    Details
    In: Frontiers in Oncology, Frontiers Media SA, Vol. 9 ( 2020-1-10)
    Type of Medium: Online Resource
    ISSN: 2234-943X
    URL: Article
    URL: Article
    DOI: 10.3389/fonc.2019.01495
    DOI: 10.3389/fonc.2019.01495.s001
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2020
    detail.hit.zdb_id: 2649216-7
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