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01.12.2012 | Research | Ausgabe 1/2012 Open Access

Molecular Cancer 1/2012

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

Zeitschrift:
Molecular Cancer > Ausgabe 1/2012
Autoren:
Liron Zehavi, Roi Avraham, Aviv Barzilai, Dalia Bar-Ilan, Roy Navon, Yechezkel Sidi, Dror Avni, Raya Leibowitz-Amit
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​1476-4598-11-44) contains supplementary material, which is available to authorized users.
Yechezkel Sidi, Dror Avni contributed equally to this work.

Competing interests

There are no financial or non-financial competing interests to declare.

Author contributions

LZ performed the molecular biology and tissue culture experiments; RA performed the micro-array experiments (with LZ); AB and DB performed the experiments with the pathological material; RN performed the bioinformatic and statistical analyses; LZ, YS, DA and RLA designed the experiments, analyzed the data and prepared the manuscript. All authors read and approved the final manuscript.

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.
Zusatzmaterial
Additional file 1: The expression levels of miRNAs in normal melanocytes and melanoma cell lines. (XLSX 68 KB)
12943_2012_1024_MOESM1_ESM.xlsx
Additional file 2: The expression levels of miRNAs in normal melanocytes, benign nevi and melanoma samples. (XLSX 92 KB)
12943_2012_1024_MOESM2_ESM.xlsx
Additional file 3: The expression levels of miRNAs in melanoma cell lines in response to epigenetic modifiers. (XLSX 59 KB)
12943_2012_1024_MOESM3_ESM.xlsx
Authors’ original file for figure 1
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Authors’ original file for figure 2
12943_2012_1024_MOESM5_ESM.pdf
Authors’ original file for figure 3
12943_2012_1024_MOESM6_ESM.pdf
Authors’ original file for figure 4
12943_2012_1024_MOESM7_ESM.pdf
Literatur
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