Abstract
BackgroundEpithelial-mesenchymal transition (EMT) has been associated with the angiogenesis and oncogenic phenotypes of multiple malignant tumors including bladder cancer (BCa). Circular RNAs (circRNAs) are recognized as crucial regulators in the EMT. This study aims to illustrate the possible role of circular RNA_0000658 (circ_0000658) in BCa and the underlying molecular mechanism.MethodsThe expression of circ_0000658, microRNA (miR)-498, and high mobility group AT-hook 2 (HMGA2) was assessed in cancer and adjacent normal tissue collected from BCa patients and human BCa cell lines (MGH-U3, T24, 5637 and SW780). BCa cells were transduced with a series of overexpression or shRNA plasmids to clarify the function of circ_0000658 and miR-498 on the oncogenic phenotypes and EMT of BCa cells. Further, we established nude mice xenografted with BCa cells to validate the roles of circ_0000658 on tumor growth in vivo.ResultsCirc_0000658 was highly expressed in BCa tissue samples and cell lines, which indicated a poor prognosis of BCa patients. Circ_0000658 competitively bound to miR-498 and thus restricted miR-498 expression. Meanwhile, circ_0000658 weakened the binding of miR-498 to the target gene HMGA2 and upregulated the HMGA2 expression. Circ_0000658 elevation or miR-498 knockdown augmented oncogenic phenotypes and EMT of BCa cells, corresponding to a reduction in the expression of β-catenin and E-cadherin as well as an increase in the expression of N-cadherin, Slug, Snail, ZEB1 and Twist. Inhibition of HMGA2 reversed the effects of circ_0000658 overexpression on tumor growth in vivo.ConclusionAltogether, our study uncovered the tumor-promoting role of circ_0000658 in BCa via the miR-498/HMGA2 axis.
Highlights
Epithelial-mesenchymal transition (EMT) has been associated with the angiogenesis and oncogenic phenotypes of multiple malignant tumors including bladder cancer (BCa)
Circular RNAs are a class of non-coding RNAs formed by covalently closed loops through backsplicing and exon-skipping, which confer pivotal effects on plenty of biological functions, acting as microRNA sponges and reservoirs, as well as combining with RNA-binding proteins during cancer progression, including BCa [6]
Circ_0000658/miR‐498/High mobility group AT-hook 2 (HMGA2) axis is predicted to play a role in the progression of BCa The differential analysis on the circRNA expression dataset GSE92675 related to BCa yielded 461 differentially expressed genes (Fig. 1A)
Summary
Epithelial-mesenchymal transition (EMT) has been associated with the angiogenesis and oncogenic phenotypes of multiple malignant tumors including bladder cancer (BCa). This study aims to illustrate the possible role of circular RNA_0000658 (circ_0000658) in BCa and the underlying molecular mechanism. Circular RNAs (circRNAs) are a class of non-coding RNAs formed by covalently closed loops through backsplicing and exon-skipping, which confer pivotal effects on plenty of biological functions, acting as microRNA (miR) sponges and reservoirs, as well as combining with RNA-binding proteins during cancer progression, including BCa [6]. CircRNAs could exert function on by binding to miRNAs; for example, circGLIS3 was demonstrated to augment BCa cell proliferative capacity by binding to miR-1273f [8]. Rarely studied in BCa, the tumor-suppressing roles of miR-498 have been revealed in other cancers [9, 10]
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