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

Abstract

// Yucui Jin 1,* , Anwen Xiong 1,2,* , Ziyu Zhang 1 , Sanen Li 1 , Huijie Huang 1 , Ting-ting Yu 1 , Xiumei Cao 1,3 and Steven Y. Cheng 1 1 Department of Developmental Genetics, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu, China 2 Department of Oncology, Changhai Hospital, Second Military Medical University, Shanghai, China 3 Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China * These authors contributed equally to this work Correspondence: Steven Y. Cheng, email: // Keywords : medulloblastoma, miR-31, tumorigenesis, MCM2, tumor cell growth Received : March 25, 2014 Accepted : May 29, 2014 Published : May 30, 2014 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.