MicroRNA-545 suppresses progression of ovarian cancer through mediating PLK1 expression by a direct binding and an indirect regulation involving KDM4B-mediated demethylation

Ke Zhang,Hailing Zhang,Zhen Xu,Jinquan Cui,Chenyang Wang,Zhilong Chen,Qian Wang

doi:10.1186/s12885-021-07830-8

Abstract

BackgroundOvarian cancer (OC) is a life-threatening gynecological malignancy where dysregulation of microRNAs (miRNAs) is frequently implicated. This study focuses on the function of miR-545 on OC development and the molecules involved.MethodsmiR-545 expression in OC tissues and cell lines was determined, and its link to the survival of patients was analyzed. Altered expression of miR-545 was induced to determine its role in proliferation, apoptosis, migration and invasion of OC cells and the angiogenesis ability of human umbilical vein endothelial cells (HUVECs). The targeting mRNAs of miR-545 were predicted and validated through luciferase assays. Gain-of-function studies of KDM4B and PLK1 were performed to explore their involvements in OC development. In vivo experiments were conducted by inducing xenograft tumors in nude mice.ResultsPoor expression of miR-545 was found in OC tissues and cells compared to the normal ones and it indicated unfavorable prognosis in patients. Overexpression of miR-545 suppressed growth, migration, invasion and angiogenesis of OC cells as well as the angiogenesis ability of HUVECs. miR-545 was found to target mRNAs of KDM4B and PLK1, while KDM4B promoted the transcription of the PLK1 promoter through demethylation of H3K9me3. Either overexpression of KDM4B or PLK1 partially blocked the inhibitory effects of miR-545 mimic on OC cell growth, especially the former one. The in vitro results were reproduced in vivo.ConclusionThis study evidenced that miR-545 suppresses progression of OC through mediating PLK1 expression by a direct binding and an indirect regulation involving KDM4B-mediated demethylation.

Highlights

Ovarian cancer (OC) is a life-threatening gynecological malignancy where dysregulation of microRNAs is frequently implicated
MicroRNAs have been increasingly accepted to impact cancer disease progression. They are small non-coding RNA molecules abundantly existed in animals and plants with the primary function in mRNA silencing through regulation of gene expression posttranscriptionally [5]. miRNAs are closely linked to nearly every carcinogenesis process from tumor development to drug resistance in human cancers including OC [6]
Polo-like kinase 1 (PLK1) and Lysine (K)-specific demethylase 4B (KDM4B), both of which have been reported to be highly expressed in OC cells and trigger cancer development [9, 10], were found as mRNA targets of miR-545 according to the data on a bioinformatic system StarBase

Summary

Introduction

Ovarian cancer (OC) is a life-threatening gynecological malignancy where dysregulation of microRNAs (miRNAs) is frequently implicated. MicroRNAs (miRNAs) have been increasingly accepted to impact cancer disease progression They are small non-coding RNA molecules (approximately 22 nucleotides in length) abundantly existed in animals and plants with the primary function in mRNA silencing through regulation of gene expression posttranscriptionally [5]. MiR-545 has been reported as a potential tumor suppressor that was poorly expressed in OC tissues [8] These findings attracted our attention to validate the role of miR-545 in OC progression and the molecules involved. Polo-like kinase 1 (PLK1) and Lysine (K)-specific demethylase 4B (KDM4B), both of which have been reported to be highly expressed in OC cells and trigger cancer development [9, 10], were found as mRNA targets of miR-545 according to the data on a bioinformatic system StarBase (http://starbase.sysu.edu.cn/). This study was performed to validate the potential interactions among miR-545, KDM4B and PLK1 and their functions on OC development by altering their expression in both cellular and animal experiments

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Results

Discussion

Conclusion