Silencing of a large microRNA cluster on human chromosome 14q32 in melanoma: biological effects of mir-376a and mir-376c on insulin growth factor 1 receptor

Molecular Cancer

Research

Roy Navon¹  Roi Avraham²  Raya Leibowitz-Amit³  Dalia Bar-Ilan⁴  Aviv Barzilai⁵  Dror Avni⁶  Liron Zehavi⁷  Yechezkel Sidi⁷ 

[1] Agilent Laboratories, Tel Aviv, Israel;Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel;Institute of Oncology, Sheba Medical Center, 52621, Tel Hashomer, Israel;Institute of Pathology, Sheba Medical Center, Tel Hashomer, Israel;Institute of Pathology, Sheba Medical Center, Tel Hashomer, Israel;Department of Dermatology, Sheba Medical Center, Tel Hashomer, Israel;Laboratory of Molecular Cell Biology, Cancer Research Center and Department of Medicine C, Sheba Medical Center, Tel Hashomer, Israel;Laboratory of Molecular Cell Biology, Cancer Research Center and Department of Medicine C, Sheba Medical Center, Tel Hashomer, Israel;Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel;

关键词: microRNA;    Melanoma;    IGF1R;    mir-376a;    mir-376c, Epigenetics;   

DOI  :  10.1186/1476-4598-11-44

 received in 2012-02-07, accepted in 2012-05-25,  发布年份 2012

来源: Springer

【 摘 要 】

BackgroundMetastatic melanoma is a devastating disease with limited therapeutic options. MicroRNAs (miRNAs) are small non coding RNA molecules with important roles in post-transcriptional gene expression regulation, whose aberrant expression has been implicated in cancer.ResultsWe show that the expression of miRNAs from a large cluster on human chromosome 14q32 is significantly down-regulated in melanoma cell lines, benign nevi and melanoma samples relative to normal melanocytes. This miRNA cluster resides within a parentally imprinted chromosomal region known to be important in development and differentiation. In some melanoma cell lines, a chromosomal deletion or loss-of-heterozygosity was observed in the cis-acting regulatory region of this cluster. In several cell lines we were able to re-express two maternally-induced genes and several miRNAs from the cluster with a combination of de-methylating agents and histone de-acetylase inhibitors, suggesting that epigenetic modifications take part in their silencing. Stable over-expression of mir-376a and mir-376c, two miRNAs from this cluster that could be re-expressed following epigenetic manipulation, led to modest growth retardation and to a significant decrease in migration in-vitro. Bioinformatic analysis predicted that both miRNAs could potentially target the 3'UTR of IGF1R. Indeed, stable expression of mir-376a and mir-376c in melanoma cells led to a decrease in IGF1R mRNA and protein, and a luciferase reporter assay indicated that the 3'UTR of IGF1R is a target of both mir-376a and mir-376c.ConclusionsOur work is the first to show that the large miRNA cluster on chromosome 14q32 is silenced in melanoma. Our results suggest that down-regulation of mir-376a and mir-376c may contribute to IGF1R over-expression and to aberrant negative regulation of this signaling pathway in melanoma, thus promoting tumorigenesis and metastasis.

【 授权许可】

Unknown   
© Zehavi et al.; licensee BioMed Central Ltd. 2012. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.