Integration of SNP and mRNA Arrays with MicroRNA Profiling Reveals That MiR-370 Is Upregulated and Targets NF1 in Acute Myeloid Leukemia

Abstract

BackgroundDeregulated miRNA expression plays a crucial role in carcinogenesis. Recent studies show different mechanisms leading to miRNA deregulation in cancer; however, alterations affecting miRNAs by DNA copy number variations (CNV) remain poorly studied.ResultsOur integrative analysis including data from high resolution SNPs arrays, mRNA expression arrays, and miRNAs expression profiles in 16 myeloid cell lines highlights that CNV are alternative mechanisms to deregulate the expression of miRNAs in acute myeloid leukemia (AML), and represent a novel approach to identify novel candidate genes involved in AML. We found association between the expression levels of 19 miRNAs and CNVs affecting their loci. Functional analysis showed that NF1 is a direct target of miR-370, and that overexpression of miR-370 has similar effects that NF1 inactivation, increasing proliferation and colony formation in AML cells. Moreover, real time RT-PCR showed that NF1 downregulation is a recurrent event in AML (30.8%), and western blot analysis confirmed this result. MiR-370 overexpression and deletions affecting the NF1 locus were identified as alternative mechanisms to downregulate NF1.Conclusions NF1 downregulation is a common event in AML, and both deletions in the NF1 locus and overexpression of miR-370 are alternative mechanisms to downregulate NF1 in this disease. Our results suggest a leukemogenic role of miR-370 through NF1 downregulation in AML cells. Since NF1 deficiency leads to RAS activation, patients with AML and overexpression of miR-370 may potentially benefit from additional treatment with either RAS or mTOR inhibitors.

MicroRNA in Alzheimer’s disease: an exploratory study in brain, cerebrospinal fluid and plasma

“…Interestingly, miR-370 has been reported to be associated with lipid metabolism, coronary artery disease as well as cell proliferation of epithelial and neuronal cell types (Chang et al, 2012; Gao et al, 2012; Garcia-Orti et al, 2012; Iliopoulos et al, 2010; Liu et al, 2012; Wu et al, 2012). MiR-328 has been described to modulate the expression of mouse beta-amyloid precursor protein-converting enzyme 1(Boissonneault et al, 2009).…”

Global Profiling in Vestibular Schwannomas Shows Critical Deregulation of MicroRNAs and Upregulation in Those Included in Chromosomal Region 14q32

“…The upregulated miRNAs in our studies include miR-21, which targets PTEN in non-small cell lung cancer [54]; cluster miR-221/miR-222, which is activated in Schwann cell proliferation following sciatic nerve injury by targeting LASS2 [55] and accelerates proliferation during liver regeneration [56]; and miR-370, which is capable of reducing NF1 mRNA levels in acute myeloid leukemia [57] and is also overexpressed in prostate cancer [58]. Another miRNA with increased expression is miR-493, which is defined as a tumor suppressor in bladder cancer and is capable of downregulating FZD4 and RhoC protein expression [59].…”

miRNA and miRNA target genes in copy number variations occurring in individuals with intellectual disability

“…Unfortunately, we do not have miRNA expression data from our CNVs as RNA was not available. However, a recent study by Garcia-Orti et al [34], demonstrated 10% of 259 studied miRNAs from regions of gain and loss detected in AML had significant change in expression concordant with the type of copy number change.…”