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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

Liron Zehavi12, Roi Avraham3, Aviv Barzilai45, Dalia Bar-Ilan4, Roy Navon6, Yechezkel Sidi12*, Dror Avni1* and Raya Leibowitz-Amit7*

Author Affiliations

1 Laboratory of Molecular Cell Biology, Cancer Research Center and Department of Medicine C, Sheba Medical Center, Tel Hashomer, Israel

2 Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

3 Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel

4 Institute of Pathology, Sheba Medical Center, Tel Hashomer, Israel

5 Department of Dermatology, Sheba Medical Center, Tel Hashomer, Israel

6 Agilent Laboratories, Tel Aviv, Israel

7 Institute of Oncology, Sheba Medical Center, Tel Hashomer, 52621, Israel

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Molecular Cancer 2012, 11:44  doi:10.1186/1476-4598-11-44

Published: 2 July 2012

Abstract

Background

Metastatic 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.

Results

We 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.

Conclusions

Our 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.

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