microRNA-451a promoter methylation regulated by DNMT3B expedites bladder cancer development via the EPHA2/PI3K/AKT axis
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RESEARCH ARTICLE
Open Access
microRNA-451a promoter methylation regulated by DNMT3B expedites bladder cancer development via the EPHA2/PI3K/ AKT axis Beibei Liu†, Wei Sun†, Wuyue Gao, Liqiang Li, Zhenxue Cao, Xiaohuai Yang, Jianmin Liu and Yuanyuan Guo*
Abstract Background: The downregulation of microRNA (miR)-451a has been reported in bladder cancer (BCa) tissues. Herein, we elucidated the role of miR-451a in BCa with the involvement of DNA methyltransferase 3B (DNMT3B). Methods: We first screened the differentially expressed miRNAs from the serum of 12 BCa patients and 10 healthy controls in the BCa database GSE113486. Subsequently, we detected miR-451a expression and CpG island methylation of the promoter in BCa cells T24 and 5637 with DNMT3B knockdown. The downstream mRNAs of miR451a were predicted by bioinformatics and KEGG enrichment analysis. Afterwards, the expression patterns of DNMT3B, miR-451a and erythropoietin-producing hepatocellular receptor tyrosine kinase class A2 (EPHA2) were altered in BCa cells to test the ability of cell proliferation, apoptosis, migration as well as invasion. Finally, the effect of miR-451a and DNMT3B was evaluated in vivo. Results: miR-451a was significantly reduced in serum of BCa patients and cell lines. Moreover, the expression of DNMT3B in BCa cells was significantly increased, thus promoting methylation of the miR-451a promoter, resulting in miR-451a inhibition. Additionally, we found that miR-451a targeted and negatively regulated EPHA2, while EPHA2 could activate the PI3K/AKT signaling, driving BCa cell growth and metastasis. Conclusions: Our study proposed and demonstrated that miR-451a downregulation mediated by DNMT3B is critical for proliferation, migration, and invasion of BCa, which may be beneficial for developing more effective therapies against BCa. Keywords: Bladder cancer, DNMT3B, microRNA-451a, EPHA2, The PI3K/AKT signaling
Background Bladder cancer (BCa), the most common and lethal cancer in the urinary system, holds accountable for estimated 81, 400 new cases and 17,980 death in the USA in 2020 [1]. BCa is divided into two main categories, muscle-invasive BCa (accounting for 25%) and non-muscle invasive BCa * Correspondence: [email protected] † Beibei Liu and Wei Sun contributed equally to this work. Department of Urology, The First Affiliated Hospital of Bengbu Medical College, No. 287, Changhuai Road, Bengbu 233000, Anhui, People’s Republic of China
(accounting for 75%), and the former one is treated by radical cystectomy, adjuvant chemotherapy or chemoradiotherapy, while the latter one is usually treated by transurethral resection and intravesical therapies [2]. About half of non-muscle invasive BCa are low grade, whereas most muscle-invasive or metastatic BCa are high grade [3]. To significantly halt the course of the malignancy, improvements should be achieved in the diagnosis and treatment of metastatic BCa. MicroRNAs (miRNAs) are endogenous ~ 23 nt RNA transcripts that play vital gene-regulatory roles in animals
© The Author(s). 2020 Open Ac
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