Tumour-suppressor microRNAs let-7 and mir-101 target the proto-oncogene MYCN and inhibit cell proliferation in MYCN-amplified neuroblastoma

被引：165

作者：

Buechner, J. ^{[1
,2
]}

Tomte, E. ^{[2
]}

Haug, B. H. ^{[2
]}

Henriksen, J. R. ^{[2
]}

Lokke, C. ^{[2
]}

Flaegstad, T. ^{[1
,2
]}

Einvik, C. ^{[1
,2
]}

机构：

[1] Univ Hosp N Norway, Dept Paediat, N-9038 Tromso, Norway

[2] Univ Tromso, Fac Hlth Sci, Dept Clin Med, Paediat Res Grp, N-9037 Tromso, Norway

来源：

BRITISH JOURNAL OF CANCER | 2011年 / 105卷 / 02期

关键词：

neuroblastoma; N-myc; MYCN; let-7; mir-101; 3 ' UTR; NEURONAL DIFFERENTIATION; N-MYC; CANCER; EXPRESSION; ONCOPROTEIN; MOLECULE; OVEREXPRESSION; REPRESSES; APOPTOSIS; PATHWAYS;

D O I：

10.1038/bjc.2011.220

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

BACKGROUND: MicroRNAs (miRNAs) regulate expression of many cancer-related genes through posttranscriptional repression of their mRNAs. In this study we investigate the proto-oncogene MYCN as a target for miRNA regulation. METHODS: A luciferase reporter assay was used to investigate software-predicted miRNA target sites in the 3'-untranslated region (3'UTR) of MYCN. The miRNAs were overexpressed in cell lines by transfection of miRNA mimics or miRNA-expressing plasmids. Mutation of the target sites was used to validate MYCN 3'UTR as a direct target of several miRNAs. To measure miRNA-mediated suppression of endogenous N-myc protein, inhibition of proliferation and inhibition of clonogenic growth, miRNAs were overexpressed in a MYCN-amplified neuroblastoma cell line. RESULTS: The results from this study show that MYCN is targeted by several miRNAs. In addition to the previously shown mir-34a/c, we experimentally validate mir-449, mir-19a/b, mir-29a/b/c, mir-101 and let-7e/mir-202 as direct MYCN-targeting miRNAs. These miRNAs were able to suppress endogenous N-myc protein in a MYCN-amplified neuroblastoma cell line. The let-7e and mir-202 were strong negative regulators of MYCN expression. The mir-101 and the let-7 family miRNAs let-7e and mir-202 inhibited proliferation and clonogenic growth when overexpressed in Kelly cells. CONCLUSION: The tumour-suppressor miRNAs let-7 and mir-101 target MYCN and inhibit proliferation and clonogenic growth of MYCN-amplified neuroblastoma cells. British Journal of Cancer (2011) 105, 296-303. doi: 10.1038/bjc.2011.220 www.bjcancer.com Published online 7 June 2011 (C) 2011 Cancer Research UK

引用

页码：296 / 303

页数：8

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