Abstract
BackgroundCircular 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.MethodscircCHST15 (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.ResultsThe 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.ConclusionsWe 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.
Highlights
Renal cell carcinoma (RCC) accounts for at least 3% of malignant diseases [1] and is the second leading cause of urological malignant neoplasm-related death [2]
CircCHST15 is upregulated in clear cell renal cell carcinoma (ccRCC) and associated with poor prognosis of patients with ccRCCTo validate the clinical relevance of circCHST15 in ccRCC, we first applied Quantitative real-time polymerase chain reaction (qRT–PCR) to detect the expression of circCHST15 in 175 pairs of ccRCC tissues and matched adjacent normal tissues
We determined that more advanced tumor grade and stage was associated with higher circCHST15 expression level, and Kaplan–Meier analysis showed that patients with tumors characterized by low circCHST15 expression had markedly better overall survival (OS) and progression-free survival (PFS) (Fig. 1H,I)
Summary
Renal cell carcinoma (RCC) accounts for at least 3% of malignant diseases [1] and is the second leading cause of urological malignant neoplasm-related death [2]. It is essential that the molecular mechanisms that promote ccRCC development and progression be further studied. Hsa_circ_001783 promoted progression of breast cancer cells via sponging miR-200c-3p [12]. CircRNA hsa_circ_002577 accelerated EC progression by acting as a miR-625-5p sponge, upregulating IGF1R and activating the PI3K/Akt pathway [14]. 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. 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
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