Abstract
Circular RNAs (circRNAs), a novel class of noncoding RNAs, have been shown to play critical regulatory roles in clear cell renal cell carcinoma (ccRCC). Metastasis is the main contributor to the poor prognosis of patients with ccRCC. However, the role of circRNAs in ccRCC metastasis has not been fully elucidated. In this study, microarray and RNA-seq analyses revealed that circPSD3 (hsa_circ_0002111) was dramatically downregulated in ccRCC tissues compared to adjacent nontumor tissues. A qRT-PCR analysis performed on our ccRCC cohorts confirmed the downregulation of circPSD3 in ccRCC tissues and further suggested that a low level of circPSD3 expression was associated with tumor metastasis in patients with ccRCC. Based on the results of functional studies, circPSD3 significantly inhibited cell migration, invasion, and the epithelial-mesenchymal transition (EMT) in vitro and blocked pulmonary metastasis in vivo. Mechanistically, circPSD3 functioned as a competing endogenous RNA for microRNA 25-3p (miR-25-3p) to regulate F-box and WD repeat domain-containing 7 (FBXW7) expression. Further verification indicated that circPSD3 overexpression restrained an EMT-like phenotype in cells, while miR-25-3p partially rescued these effects. In summary, circPSD3 inhibits tumor metastasis by repressing the miR-25-3p/FBXW7-EMT axis and might be developed as a potential diagnostic and therapeutic target for ccRCC.
Highlights
Renal cell carcinoma (RCC) has the highest lethality rate among urological tumors [1], and its incidence and mortality rates are increasing yearly
CD10 is considered a metastatic marker for Clear cell renal cell carcinoma (ccRCC) [19]. e levels of circPSD3 were significantly downregulated in metastatic ccRCC tissues compared with those in nonmetastatic ccRCC tissues (P < 0.001) (Figure 2(b))
We established a receiver operating characteristic (ROC) curve (68 tissues from patients without metastatic ccRCC were used as a control) and found that circPSD3 was highly correlated with ccRCC metastasis. e area under the ROC curve was 0.824 (P < 0.001) (Figure 2(e))
Summary
Renal cell carcinoma (RCC) has the highest lethality rate among urological tumors [1], and its incidence and mortality rates are increasing yearly. The mechanisms underlying ccRCC metastasis must be Journal of Oncology elucidated to promote the further development of novel diagnostic and therapeutic strategies. E biological functions and roles of circRNAs have been reported in all kinds of different cancers, suggesting the potential of circRNAs as biomarkers and therapeutic targets [10, 11]. Numerous studies have reported various functions of circRNAs, which serve as microRNA (miRNA) sponges by directly binding miRNAs [12]. CircASAP is upregulated in hepatocellular carcinoma (HCC) and accelerates HCC cell metastasis by combining miR-326 and miR-532-5p, thereby regulating the expressions of MAPK1 and CSF-1 [13]. Circ-AKT3 inhibits ccRCC cell metastasis by competitively sponging miR-296-3p and upregulating E-cadherin [14]. Mitochondria-specific circRNA (SCAR) was reported as a therapeutic target for NASH by reducing mitochondrial reactive oxygen species (MROS) output, fibroblast activation, and inflammatory response [17]. Many mechanisms and functions of circRNAs in ccRCC remain unclear
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