The MYCN oncogene is a direct target of miR-34a

Abstract

Loss of 1p36 heterozygosity commonly occurs with MYCN amplification in neuroblastoma tumors, and both are associated with an aggressive phenotype. Database searches identified five microRNAs that map to the commonly deleted region of 1p36 and we hypothesized that the loss of one or more of these microRNAs contributes to the malignant phenotype of MYCNamplified tumors. By bioinformatic analysis, we identified that three out of the five microRNAs target MYCN and of these miR-34a caused the most significant suppression of cell growth through increased apoptosis and decreased DNA synthesis in neuroblastoma cell lines with MYCN amplification. Quantitative RT-PCR showed that neuroblastoma tumors with 1p36 loss expressed lower level of miR-34a than those with normal copies of 1p36. Furthermore, we demonstrated that MYCN is a direct target of miR-34a. Finally, using a series of mRNA expression profiling experiments, we identified other potential direct targets of miR-34a, and pathway analysis demonstrated that miR-34a suppresses cell-cycle genes and induces several neural-related genes. This study demonstrates one important regulatory role of miR-34a in cell growth and MYCN suppression in neuroblastoma.

The miR-34 family in cancer and apoptosis

“…41 Interestingly, N-MYC, which is deregulated in the neuroblastoma, is a direct target of miR-34a. 55 The correlation between 1p36 loss and miR-34a downregulation in the neuroblastoma was confirmed in this study. Furthermore, the expression of miR-34a was low or undetectable in 11 of 15 pancreatic cancer cell lines 31 and the expression level of miR-34b was decreased by more than 90% in 6 out of 14 non-small cell lung cancer.…”

Inactivation of miR-34a by aberrant CpG methylation in multiple types of cancer

“…24 Furthermore, miR-34a was identified as the candidate tumor suppressor gene in neuroblastoma and has been shown to target N-MYC. 25,26 Another report showed that CDK6 and Cyclin D1 are targets of miR-34a in the lung cancer cell line A549. 27 The high frequency of miR-34a silencing in tumors described here together with its previously identified functions suggest that miR-34a represents a tumor suppressor gene.…”

CASZ1, a candidate tumor-suppressor gene, suppresses neuroblastoma tumor growth through reprogramming gene expression

“…Previous studies showed that there are at least three discrete regions at chr1p are commonly deleted in NB, which indicates that these regions harbor putative tumorsuppressor genes. 1 Recent evidence indicates that CHD5 (1p36.31) a chromatin remodeling gene, 18,19 KIF1b (1p36.21) a pro-apoptotic gene 20,21 and miR-34a, a micro RNA known to regulate MYCN expression 22,23 are candidate 1p36 NB tumor-suppressor genes. CASZ1 (1p36.22) localizes to one of the commonly deleted region in NB on chr1p between the markers D1S508 and D1S244.…”