MiR-92b inhibitor promoted glioma cell apoptosis via targeting DKK3 and blocking the Wnt/beta-catenin signaling pathway

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MiR-92b inhibitor promoted glioma cell apoptosis via targeting DKK3 and blocking the Wnt/beta-catenin signaling pathway Qifeng Li1, Ke Shen2, Yang Zhao1, Chenkai Ma1, Jianwen Liu2 and Jie Ma1*

Abstract Background: MiR-92b was upregulated in gliomas. However, the association of miR-92b with glioma cell apoptosis and survival remains unknown. Methods: Proliferation capability of glioma cells upon tranfection with miR-92b mimics or inhibitors was detected by mutiple analyses, including MTT assays, colony formation assay. Apoptosis abilities of glioma cells were detected by flow cytometric analysis. The target of miR-92b was determined by luciferase reporter and western blot. The association of miR-92b with outcome was examined in twenty glioma patients. Results: MiR-92b expression was significantly increased in high-grade gliomas compared with low-grade gliomas, and positively correlated with the degree of glioma infiltration. Over-expression of miR-92b increased cell proliferation, whereas knockdown of miR-92b decreased cell proliferation via modulating the levels of the target, Target prediction analysis and a dual luciferase reporting assay confirmed that the inhibitory protein-coding Dickkopf-3 gene (DKK3) was a direct target of miR-92b. Furthermore, miR-92b could regulate the expression of downstream genes of the Wnt/beta-catenin signaling pathway, such as Bcl2, c-myc and p-c-Jun, in glioma cells. Finally, the increased level of miR-92b expression in high-grade gliomas confers poorer overall survival. Conclusions: The present data indicates that miR-92b directly regulate cell proliferation and apoptosis by targeting DKK3 and act as prognostic factors for glioma patients. Keywords: miR-92b, DKK3, The Wnt/beta-catenin signaling pathway, Glioma, Prognosis

Introduction A glioma is the most common form of neural malignancy. High grade glioma, especially glioblastoma, is a leading cause of brain cancer fatality involving highly invasive and neoplastic growth. Despite therapeutic advances, many patients suffer from tumor recurrence due to chemo- and radio- therapy resistance [1-3]. Increasing evidence suggests that the progression of a glioma is relative to the rate of both cell proliferation and apoptosis. Therefore, understanding the main regulatory mechanism of gliomas is key to the development of effective therapeutic approaches against this malignancy.

* Correspondence: [email protected] 1 Department of Pediatric Neurosurgery, Xinhua Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai 200092, P R China Full list of author information is available at the end of the article

MicroRNAs (miRNAs) are small, endogenous, non-coding RNA molecules, which usually result in gene silencing by binding to complementary sequences in the three prime untranslated regions (3-UTRs) of target messenger RNA transcripts (mRNAs) [4-9]. The deregulation of miRNAs has been observed in various types of human malignancies, including lymphoma, colorectal cancer, lung cancer, breast cancer, papilla