scholarly journals HIF1α is not a target of 14q deletion in clear cell renal cancer

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Niraj Shenoy
Keyword(s):  
Gene Expression ◽  
Tumor Suppressor ◽  
Protein Expression ◽  
Survival Data ◽  
Clear Cell ◽  
Genetic Manipulation ◽  
The Cancer Genome Atlas ◽  
Cell Renal Cell Carcinoma ◽  
Survival Difference

Abstract HIF1α has been termed a tumor-suppressor in clear cell renal cell carcinoma (ccRCC), primarily based on functional proliferation studies in cell lines (in vitro and in vivo) with genetic manipulation, and the adverse prognosis of 14q-deleted ccRCC patients. In other malignancies, however, HIF1α has an established tumor-promoting role. Therefore, this study sought to further examine the role of HIF1α in ccRCC using bioinformatic analyses of 530 ccRCC patients from The Cancer Genome Atlas (TCGA) and The Cancer Proteome Atlas (TCPA) registries. Although lower copy numbers of HIF1A (encoding HIF1α, located at 14q23.2) was associated with worse survival, there was no survival difference based on either HIF1A mRNA or HIF1α protein expression. Interestingly, L2HGDH (L-2-Hydroxyglutarate Dehydrogenase), a recently characterized epigenetic modulating ccRCC tumor-suppressor with a marked impact on survival, was found to be located only ~ 11.5Mbp from HIF1A on 14q (at 14q21.3). L2HGDH was therefore co-deleted in ~ 95% of 14q deletions involving HIF1A locus. Remarkably, HIF1A CNV had a markedly stronger correlation with L2HGDH expression (Rho = 0.55) than its own gene expression (Rho = 0.27), indicating high preserved-allele compensation of HIF1A. Genetic loss of HIF1A was therefore associated with a much greater reduction of L2HGDH gene expression than its own gene expression, providing a possible explanation for survival differences based on HIF1A CNV and mRNA expression. Furthermore, in 14q-deleted ccRCC patients with complete (uncensored) survival data, in the relatively rare cases where genetic loss of HIF1A occurred without genetic loss of L2HGDH (n = 5), the survival was significantly greater than where there was simultaneous genetic loss of both (n = 87) (mean survival 1670.8 ± 183.5 days vs 885.1 ± 78.4 days; p = 0.007). In addition, there was no correlation between HIF1A mRNA and HIF1α protein expression in ccRCC (R = 0.02), reflecting the primarily post-translational regulation of HIF1α. Lastly, even between L2HGDH and HIF1A loci, 14q was found to have several other yet-to-be-characterized potential ccRCC tumor-suppressors. Taken together, the data indicate that HIF1α is not a target of 14q deletion in ccRCC and that it is not a tumor-suppressor in this malignancy.

scholarly journals Long Non-Coding RNA LINC02747 Promotes the Proliferation of Clear Cell Renal Cell Carcinoma by Inhibiting miR-608 and Activating TFE3

2020 ◽  
Vol 10 ◽  
Author(s):  
Xiang Ju ◽  
Yangyang Sun ◽  
Feng Zhang ◽  
Xiaohui Wei ◽  
Zhenguo Wang ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Histological Grade ◽  
Rapid Development ◽  
The Cancer Genome Atlas ◽  
Cell Renal Cell Carcinoma

With the rapid development of biotechnology, long noncoding RNAs (lncRNAs) have exhibited good application prospects in the treatment of cancer, and they may become new treatment targets for cancer. This study aimed to explore lncRNAs in clear cell renal cell carcinoma (ccRCC). Differentially expressed lncRNAs in 54 pairs of ccRCC tissues and para-carcinoma tissues were analyzed in The Cancer Genome Atlas (TCGA), and the most significant lncRNAs were selected and verified in ccRCC tissues. We found that lncRNA LINC02747 was highly expressed in ccRCC (P < 0.001) and was closely related to high TNM stage (P = 0.006) and histological grade (P = 0.004) and poor prognosis of patients (P < 0.001). In vivo and in vitro experiments confirmed that LINC02747 could promote the proliferation of ccRCC cells. We also found that LINC02747 regulated the proliferation of RCC cells by adsorbing miR-608. Subsequent mechanistic research showed that miR-608 is downregulated in ccRCC (P < 0.001), and overexpression of miR-608 inbibited the proliferation of RCC cells. Moreover, we found that TFE3 is a direct target gene of miR-608. MiR-608 regulated the proliferation of RCC cells by inhibiting TFE3. In conclusion, LINC02747 upregulates the expression of TFE3 by adsorbing miR-608, ultimately promoting the proliferation of ccRCC cells. The above findings indicate that LINC02747 acts as an oncogene in ccRCC and may be developed as a molecular marker for the diagnosis and prognosis of ccRCC. The LINC02747/miR-608/TFE3 pathway may become a new therapeutic target for ccRCC.

scholarly journals EVI1 as a Prognostic and Predictive Biomarker of Clear Cell Renal Cell Carcinoma

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 300 ◽  
Author(s):  
Luis Palomero ◽  
Lubomir Bodnar ◽  
Francesca Mateo ◽  
Carmen Herranz-Ors ◽  
Roderic Espín ◽  
...  
Keyword(s):  
Gene Expression ◽  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Transcriptional Control ◽  
Clear Cell ◽  
Predictive Biomarker ◽  
The Cancer Genome Atlas ◽  
Cell Renal Cell Carcinoma ◽  
Immunohistochemical Studies

The transcription factor EVI1 plays an oncogenic role in several types of neoplasms by promoting aggressive cancer features. EVI1 contributes to epigenetic regulation and transcriptional control, and its overexpression has been associated with enhanced PI3K-AKT-mTOR signaling in some settings. These observations raise the possibility that EVI1 influences the prognosis and everolimus-based therapy outcome of clear cell renal cell carcinoma (ccRCC). Here, gene expression and protein immunohistochemical studies of ccRCC show that EVI1 overexpression is associated with advanced disease features and with poorer outcome—particularly in the CC-e.3 subtype defined by The Cancer Genome Atlas. Overexpression of an oncogenic EVI1 isoform in RCC cell lines confers substantial resistance to everolimus. The EVI1 rs1344555 genetic variant is associated with poorer survival and greater progression of metastatic ccRCC patients treated with everolimus. This study leads us to propose that evaluation of EVI1 protein or gene expression, and of EVI1 genetic variants may help improve estimates of prognosis and the benefit of everolimus-based therapy in ccRCC.

scholarly journals Transcriptomic characterization and innovative molecular classification of clear cell renal cell carcinoma in the Chinese population

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Qiang Zhao ◽  
Jia Xue ◽  
Baoan Hong ◽  
Wubin Qian ◽  
Tiezhu Liu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Chinese Population ◽  
Clear Cell ◽  
Expression Profiles ◽  
Molecular Classification ◽  
The Cancer Genome Atlas ◽  
Cell Renal Cell Carcinoma

Abstract Background Large-scale initiatives like The Cancer Genome Atlas (TCGA) performed genomics studies on predominantly Caucasian kidney cancer. In this study, we aimed to investigate genomics of Chinese clear cell renal cell carcinoma (ccRCC). Methods We performed whole-transcriptomic sequencing on 55 tumor tissues and 11 matched normal tissues from Chinese ccRCC patients. We systematically analyzed the data from our cohort and comprehensively compared with the TCGA ccRCC cohort. Results It found that PBRM1 mutates with a frequency of 11% in our cohort, much lower than that in TCGA Caucasians (33%). Besides, 31 gene fusions including 5 recurrent ones, that associated with apoptosis, tumor suppression and metastasis were identified. We classified our cohort into three classes by gene expression. Class 1 shows significantly elevated gene expression in the VEGF pathway, while Class 3 has comparably suppressed expression of this pathway. Class 2 is characterized by increased expression of extracellular matrix organization genes and is associated with high-grade tumors. Applying the classification to TCGA ccRCC patients revealed better distinction of tumor prognosis than reported classifications. Class 2 shows worst survival and Class 3 is a rare subtype ccRCC in the TCGA cohort. Furthermore, computational analysis on the immune microenvironment of ccRCC identified immune-active and tolerant tumors with significant increased macrophages and depleted CD4 positive T-cells, thus some patients may benefit from immunotherapies. Conclusion In summary, results presented in this study shed light into distinct genomic expression profiles in Chinese population, modified the stratification patterns by new molecular classification, and gave practical guidelines on clinical treatment of ccRCC patients.

Mammalian SIRT4 is a tumor suppressor of clear cell renal cell carcinoma by inhibiting cancer proliferation, migration and invasion

2020 ◽  
Vol 29 (4) ◽  
pp. 453-462 ◽  
Author(s):  
Changming Wang ◽  
Chiyuan Piao ◽  
Junlong Liu ◽  
Zhe Zhang ◽  
Yuyan Zhu ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Tumor Suppressor ◽  
Cell Carcinoma ◽  
Survival Data ◽  
Renal Cell ◽  
Clear Cell ◽  
Expression Level ◽  
Migration And Invasion ◽  
Advanced Tumor Stage ◽  
Cell Renal Cell Carcinoma

OBJECTIVE: Sirtuins family are defined as class III histone deacetylases (HDACs). Recently, mammalian silent information regulator two 4 (SIRT4) has been reported to be a tumor suppressor gene in multiple cancers. The objective of the present study was to explore the potential role of SIRT4 in clear cell renal cell carcinoma (ccRCC). METHODS: We estimated SIRT4 expression levels in ccRCC and its adjacent non-neoplastic tissue by Western blotting (WB), quantitative real-time polymerase chain reaction (qRT-PCR) and bioinformatics data, the clinical and survival data were also collected and analyzed. In vitro study, ccRCC cell lines were transfected with SIRT4-siRNA or lentivirus to downregulate or overexpress the expression level of SIRT4. Then, the proliferation capacity of tumor cell was assessed by 5-Ethynyl-2’-deoxyuridine (EDU) assay, cell migration and invasion capacity were assessed by Transwell assays. RESULTS: Our results indicated that the expression level of SIRT4 in ccRCC was significantly lower than the corresponding normal tissues (P< 0.001). Meanwhile, bioinformatics data and the result of WB showed that low SIRT4 expression level was obviously involved with poor overall survival and advanced tumor stage in ccRCC patients. Biological experiments demonstrated that overexpression of SIRT4 significantly reduced the proliferation, migration and invasion ability of ccRCC cells. Conversely, downregulation of SIRT4 enhanced the proliferation, migration and invasion ability of ccRCC cells. CONCLUSIONS: These findings support that SIRT4 acts as a tumor suppressor in ccRCC and might be a novel biomarker and new therapeutic target for ccRCC.

Validation of an inverse association between programmed death ligand 1 (PDL1) and genes in the vascular endothelial growth factor (VEGF) pathway in primary clear cell renal cell (ccRCC).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 4567-4567 ◽  
Author(s):  
Richard Wayne Joseph ◽  
Mansi Parasramka ◽  
Daniel Serie ◽  
Jeanette Eckel-Passow ◽  
E Aubrey Thompson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Expression ◽  
Renal Cell ◽  
Clear Cell ◽  
Fold Change ◽  
Inverse Association ◽  
Cell Renal Cell Carcinoma ◽  
Anti Vegf ◽  
Vegf Pathway ◽  
Key Genes

4567 Background: Trials combining anti-PDL1 and anti-VEGF therapies for clear cell renal cell carcinoma (ccRCC) are underway; however the relationship between the expression of PDL1 and genes in the VEGF pathway is poorly understood. Using the Affymetrix platform, we observed an inverse association between the expression of PDL1 and key genes in the VEGF pathway. Herein, we validate this inverse association using an independent set of 100 primary ccRCC tumors. Methods: From our registry database we sampled 100 ccRCC tumors with varying PDL1 protein expression (0%-100%) determined by immunohistochemistry (IHC). We extracted RNA from FFPE slides and performed RT-PCR to quantify gene expression of PDL1, VEGF, VEGFR1, and VEGFR2. All genes were normalized to the POLR2a gene. We evaluated the association of PDL1 protein expression and VEGF gene expression using Spearman rank correlation. In addition, we employed a linear mixed effects model to compare the fold-change in expression of VEGF genes between PDL1 low (0-5%, n=68) and PDL1 high (>5%, n=32) tumors. Results: As expected, PDL1 protein expression positively correlates with PDL1 geneexpression (corr=0.42, p<0.001). Validating our array data, PDL1 protein expression inversely correlates with expression of key VEGF genes: VEGF (corr=-0.23, p=0.01), VEGFR1 (corr=-0.34, p<0.001), and VEGFR2 (corr=-0.23, p=0.01). In our dichotomized analysis, we noted significantly higher expression of VEGF genes in the PDL1 low compared to the PDL1 high group: VEGF (fold change=1.82, p<0.001), VEGFR1 (FC=2.63, p<0.001), and VEGFR2 (FC=2.13, p=0.001). Conclusions: We independently validate an inverse association between the expression of PDL1 and key genes in the VEGF pathway in primary ccRCC. If validated further in larger studies, the existence of an immune evasive and an angiogenic phenotype within ccRCC could inform current clinical trials targeting these two pathways. Ultimately, whether VEGF signaling affects PDL1 expression, or whether angiogenic or immune evasive phenotypes predict response to anti-PDL1, anti-VEGF, or a combination of the two therapies remains unclear.

Toward a molecular genetic classification of clear cell renal cell carcinoma.

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 341-341
Author(s):  
James Brugarolas ◽  
Payal Kapur ◽  
Samuel Pena-Llopis ◽  
Alana Christie ◽  
Xian-Jin Xie
Keyword(s):  
Gene Expression ◽  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
The Cancer Genome Atlas ◽  
Genetic Classification ◽  
Cell Renal Cell Carcinoma ◽  
Fuhrman Grade ◽  
Pathologic Features

341 Background: Clear cell renal cell carcinoma (ccRCC) displays a variety of clinical behaviors. However, the molecular underpinnings are unknown. We discovered that BAP1 is mutated in approximately 15% of ccRCC and that BAP1 and PBRM1mutations are largely mutually exclusive. Herein, we investigate the clinicopathological significance of these molecular subtypes. Methods: Tumors from 145 patients with primary ccRCC were sequenced for PBRM1 and BAP1. Tumors were classified into BAP1-mutated and those exclusively mutated for PBRM1. Tumors were evaluated for pathologic features, gene expression and associated outcomes. A second independent cohort (n=327) from The Cancer Genome Atlas (TCGA) was used for validation. Results: When compared to PBRM1-mutant tumors, BAP1-mutant tumors were associated with aggressive pathological features including high Fuhrman grade and tumor necrosis. BAP1-mutant and PBRM1-mutant tumors exhibited distinct gene expression signatures. The median overall survival (OS) was shorter for patients with BAP1-mutant tumors (4.6 years; 95% CI, 2.1-7.2), than for patients with PBRM1-mutant tumors (10.6 years; 95% CI, 9.8-11.5), corresponding to a hazard ratio (HR) of 2.7 (95% CI, 0.99-7.6, p = 0.044). A similar HR was observed in the independent dataset from the TCGA (2.8; 95% CI, 1.4-5.9; p = 0.004). The BAP1-mutant group could be further subdivided into tumors with mutations exclusively in BAP1 and those with mutations in both BAP1 and PBRM1. Double mutant tumors constituted a minority (n = 4; in TCGA), and were associated with the shortest OS (HR, 10; 95% CI, 3.2-33.6). Conclusions: Our findings reveal novel biological subgroups of ccRCC with distinct clinical outcomes, a high-risk BAP1-mutant group and a favorable PBRM1-mutant group. These data establish the basis for a molecular subclassification of ccRCC that could influence treatment decisions in the future.

scholarly journals CCR5 blockade inflames antitumor immunity in BAP1-mutant clear cell renal cell carcinoma

2020 ◽  
Vol 8 (1) ◽  
pp. e000228
Author(s):  
Quan Zhou ◽  
Yangyang Qi ◽  
Zewei Wang ◽  
Han Zeng ◽  
Hongyu Zhang ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
T Cells ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
The Cancer Genome Atlas ◽  
In Vivo Studies ◽  
Cell Renal Cell Carcinoma ◽  
Ccr5 Blockade

BackgroundPatients with BRCA1-associated protein 1 (BAP1)-mutant clear cell renal cell carcinoma (ccRCC) have worse prognosis. C-C chemokine receptor 5 (CCR5) plays an important role in ccRCC development and its expression is elevated in BAP1-mutant tumors.Methods533 patients with ccRCC from The Cancer Genome Atlas cohort and 797 patients with ccRCC from the Shanghai cohort were enrolled. In vitro and in vivo studies were conducted with human ccRCC tumors and murine tumor models. The association between BAP1 and CCR5 or its ligands was assessed by immunohistochemistry, flow cytometry, real-time PCR and ELISA. Survival was compared between different subpopulations of patients using Kaplan-Meier curve. Therapeutic effect of CCR5 blockade was validated using human ccRCC tumors and murine models.ResultsExpression of CCR5 and its ligands were elevated in BAP1-mutant patients with ccRCC. High CCR5 expression was indicative of poor prognosis in BAP1-low group of patients. CCR5 blockade prolonged the survival of tumor-bearing mice, resulting in enhanced cytotoxicity of T cells and antigen presentation of dendritic cells but repressed immune checkpoint expression. CCR5 ligands could recruit CCR5+regulatory T cells to the tumor microenvironment. Additionally, BAP1-mutant ccRCC tumor cells secreted CCR5 ligands, which increased programmed cell death ligand 1 expression. However, both processes could be inhibited by CCR5 blockade. Study limitations include the unclear impact of CCR5 expressed by other cell populations.ConclusionsCCR5 in BAP1-mutant ccRCC results in an immune-suppressive microenvironment. Targeting CCR5 could provide a potential therapeutic benefit for patients.Trial registration numberNCT01358721, CA209-009.

scholarly journals Multicenter Validation of Enhancer of Zeste Homolog 2 Expression as an Independent Prognostic Marker in Localized Clear Cell Renal Cell Carcinoma

2017 ◽  
Vol 35 (32) ◽  
pp. 3706-3713 ◽  
Author(s):  
Thai Huu Ho ◽  
Payal Kapur ◽  
Jeanette E. Eckel-Passow ◽  
Alana Christie ◽  
Richard W. Joseph ◽  
...  
Keyword(s):  
Protein Expression ◽  
Mayo Clinic ◽  
Clear Cell ◽  
Medical Center ◽  
High Protein ◽  
The Cancer Genome Atlas ◽  
Cell Renal Cell Carcinoma ◽  
University Of Texas ◽  
Cancer Genome Atlas ◽  
Low Expression

Purpose Enhancer of zeste homolog 2 (EZH2), a chromatin remodeler, is implicated in the pathogenesis of clear cell renal cell carcinoma (ccRCC). However, the effect of EZH2 on outcomes in localized ccRCC is unclear, and molecular biomarkers are not currently integrated into prognostic models or adjuvant therapy trials. Methods We performed Cox regression to evaluate the association of tumor-based EZH2 gene and protein expression with survival in three independent cohorts: a cohort from The Cancer Genome Atlas (n = 532), a cohort from University of Texas Southwestern Medical Center (n = 122), and a cohort from Mayo Clinic (n = 1,338). Analyses were adjusted for the prognostic stage, size, grade, and necrosis (SSIGN) score as well as within low-, intermediate-, and high-risk SSIGN groups. Results Patients in The Cancer Genome Atlas cohort with EZH2-high gene expression were 1.5 times more likely to experience overall death than patients with EZH2-low expression (95% CI, 1.1 to 2.3; P = .028). Patients in the University of Texas Southwestern Medical Center cohort with EZH2-high protein expression were two times more likely to experience overall death than patients with EZH2-low expression (95% CI, 1.1 to 4.4; P = .034). Similarly, patients in the Mayo Clinic cohort with EZH2-high protein expression were 1.4 times more likely to experience overall death (95% CI, 1.2 to 1.7; P < .001). Patients in the Mayo Clinic cohort with EZH2-high protein expression were nearly two times more likely to experience RCC-specific death (95% CI, 1.5 to 2.6; P < .001); EZH2 protein expression was particularly prognostic among patients with low-risk SSIGN tumors (HR, 6.1; 95% CI, 3.4 to 11.1; P < .001). Conclusion EZH2 expression accurately predicts risk of RCC death beyond existing clinicopathologic models, particularly in low- and intermediate-risk SSIGN tumors. Further studies are required to incorporate molecular biomarkers into surveillance guidelines and adjuvant clinical trials.

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 circCHST15 is a novel prognostic biomarker that promotes clear cell renal cell carcinoma cell proliferation and metastasis through the miR-125a-5p/EIF4EBP1 axis

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Cheng-Peng Gui ◽  
Bing Liao ◽  
Cheng-Gong Luo ◽  
Yu-Hang Chen ◽  
Lei Tan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Prognostic Biomarker ◽  
Cell Renal Cell Carcinoma ◽  
Proliferation And Metastasis

Abstract Background Circular RNAs (circRNAs) have been indicated as potentially critical mediators in various types of tumor progression, generally acting as microRNA (miRNA) sponges to regulate downstream gene expression. However, the aberrant expression profile and dysfunction of circRNAs in human clear cell renal cell carcinoma (ccRCC) need to be further investigated. This study mined key prognostic circRNAs and elucidates the potential role and molecular mechanism of circRNAs in regulating the proliferation and metastasis of ccRCC. Methods circCHST15 (hsa_circ_0020303) was identified by mining two circRNA microarrays from the Gene Expression Omnibus database and comparing matched tumor versus adjacent normal epithelial tissue pairs or matched primary versus metastatic tumor tissue pairs. These results were validated by quantitative real-time polymerase chain reaction and agarose gel electrophoresis. We demonstrated the biological effect of circCHST15 in ccRCC both in vitro and in vivo. To test the interaction between circCHST15 and miRNAs, we conducted a number of experiments, including RNA pull down assay, dual-luciferase reporter assay and fluorescence in situ hybridization. Results The expression of circCHST15 was higher in ccRCC tissues compared to healthy adjacent kidney tissue and higher in RCC cell lines compared to normal kidney cell lines. The level of circCHST15 was positively correlated with aggressive clinicopathological characteristics, and circCHST15 served as an independent prognostic indicator for overall survival and progression-free survival in patients with ccRCC after surgical resection. Our in vivo and in vitro data indicate that circCHST15 promotes the proliferation, migration, and invasion of ccRCC cells. Mechanistically, we found that circCHST15 directly interacts with miR-125a-5p and acts as a microRNA sponge to regulate EIF4EBP1 expression. Conclusions We found that sponging of miR-125a-5p to promote EIF4EBP1 expression is the underlying mechanism of hsa_circ_0020303-induced ccRCC progression. This prompts further investigation of circCHST15 as a potential prognostic biomarker and therapeutic target for ccRCC.

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