MicroRNA-31 suppresses medulloblastoma cell growth by inhibiting DNA replication through minichromosome maintenance 2.

Yucui Jin,Xiumei Cao,Anwen Xiong,Steven Y Cheng,Sanen Li,Ziyu Zhang,Ting-Ting Yu,Huijie Huang

doi:10.18632/oncotarget.2043

Abstract

Medulloblastoma is an aggressive childhood brain tumor with poor prognosis. Recent studies indicate that dys-regulation of microRNA expression plays important roles in tumorigenesis. By comparing microRNA levels between mouse medulloblastoma and normal cerebellar tissues, we identified a set of down-regulated microRNAs including miR-31. Here, we show that the genomic region surrounding human miR-31 at 9p21.3 is frequently deleted in many solid tumor cell lines, and reintroducing miR-31 into DAOY cells, a line of human medulloblastoma cells devoid of miR-31, strongly suppresses cell growth, causes cell cycle arrest at the G1/S boundary, and inhibits colony formation in vitro and xenograft tumorigenesis in nude mice. Global gene expression profiling of mouse medulloblastomas and bioinformatics analyses of microRNA targets suggest that minichromosome maintenance complex component 2 (MCM2) is a likely target gene of miR-31 in suppressing cell growth. We demonstrate that miR-31 inhibits MCM2 expression via its 3'-untranslated region, that knockdown of MCM2 in DAOY cells leads to a degree of growth inhibition comparable to that by miR-31 restoration, and that overexpression of miR-31 reduces the chromatin loading of MCM2 at the point of G1/S transition. Taken together, these data indicate that miR-31 suppresses medulloblastoma tumorigenesis by negatively regulating DNA replication via MCM2.

Highlights

Most cancers arise in old ages as the consequence of accumulative genetic lesions in the genome [1]
We demonstrate that miR-31 inhibits maintenance complex component 2 (MCM2) expression via its 3’-untranslated region, that knockdown of MCM2 in DAOY cells leads to a degree of growth inhibition comparable to that by miR-31 restoration, and that overexpression of miR-31 reduces the chromatin loading of MCM2 at the point of G1/S transition
Twenty-four miRNAs were up-regulated and 128 miRNAs showed down-regulation in medulloblastoma. One of these microRNAs is miR31 that has been shown previously to play an important role in metastasis [22, 24], and reported as being down-regulated in human medulloblastomas compared to normal cerebella [28]

Summary

Introduction

Most cancers arise in old ages as the consequence of accumulative genetic lesions in the genome [1]. Recent cancer whole genome sequencing studies indicate that, on average, human solid adult tumors can have mutations affecting over 100 genes [2]; most of these cancer associated genes are altered by noncancer-causing passenger mutations. Pediatric cancers, which occur early in life and are rare, have much fewer genetically altered genes, making them ideal places for finding cancer-causing driver mutations. Recent mouse model studies have identified two populations of cells, namely the granule neuron progenitors in the external germinal layer and the multipluripotent neural stem cells likely from the dorsal brain stem [4], as the cellular origin of medulloblastoma. Medulloblastoma has been classified into four subtypes based on global gene expression profiling and DNA copy number analyses; these include tumors with aberrant regulation in the WNT and Sonic Hedgehog (SHH) pathways as well as two other less defined Group www.impactjournals.com/oncotarget

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