Upregulation of the microRNA cluster at the Dlk1-Dio3 locus in lung adenocarcinoma

Abstract

Mice in which lung epithelial cells can be induced to express an oncogenic KrasG12D develop lung adenocarcinomas in a manner analogous to humans. A myriad of genetic changes accompany lung adenocarcinomas, many of which are poorly understood. To get a comprehensive understanding of both the transcriptional and post-transcriptional changes that accompany lung adenocarcinomas, we took an omics approach in profiling both the coding genes and the non-coding small RNAs in an induced mouse model of lung adenocarcinoma. RNAseq transcriptome analysis of KrasG12D tumors from F1 hybrid mice revealed features specific to tumor samples. This includes the repression of a network of GTPase related genes (Prkg1, Gnao1 and Rgs9) in tumor samples and an enrichment of Apobec1-mediated cytosine to uridine RNA editing. Furthermore, analysis of known SNPs revealed not only a change in expression of Cd22 but also that its expression became allele-specific in tumors. The most salient finding however, came from small RNA sequencing of the tumor samples, which revealed that a cluster of ~53 microRNAs and mRNAs at the Dlk1-Dio3 locus on mouse chromosome 12qF1 was dramatically and consistently increased in tumors. Activation of this locus occurred specifically in sorted tumor-originating cancer cells. Interestingly, the 12qF1 RNAs were repressed in cultured KrasG12D tumor cells but reactivated when transplanted in vivo. These microRNAs have been implicated in stem cell pleuripotency and proteins targeted by these microRNAs are involved in key pathways in cancer as well as embryogenesis. Taken together our results strongly imply that these microRNAs represent key targets in unraveling the mechanism of lung oncogenesis.

A MicroRNA Cluster at 14q32 Drives Aggressive Lung Adenocarcinoma

“…Indeed, they were overexpressed in the lungs of mice at the late embryonic stage or newborn mice and then decrease dramatically during the first weeks of life (45,46). A recent study that performed RNAseq in KRAS G12D transgenic tumors found that miRNAs encoded at the Dlk1-Dio3 locus on mouse chromosome 12qF1 were consistently increased in tumors as compared with nonmalignant lung (47). Interestingly, these miRNAs were repressed when KRAS G12D cells were grown in vitro and were reactivated when transplanted in vivo.…”

miR-154* and miR-379 in the DLK1-DIO3 MicroRNA Mega-Cluster Regulate Epithelial to Mesenchymal Transition and Bone Metastasis of Prostate Cancer

“…During mouse embryogenesis, the microRNA (miRNA) members of the DLK1-DIO3 cluster have been shown to be elevated in the developing central nervous system, skeletal muscle, liver and lung (3). Similarly, several transgenic mouse models of prostate, liver and lung cancer also exhibit elevated levels of DLK1-DIO3 cluster miRNA members (4–8). The functions of many of these miRNAs within this imprinted region remain largely unexplored in cancer biology, specifically for EMT and cancer stemness.…”

The RNA-editing Enzyme APOBEC1 Requires Heterogeneous Nuclear Ribonucleoprotein Q Isoform 6 for Efficient Interaction with Interleukin-8 mRNA

“…By contrast, Greeve et al (8) have suggested that most types of carcinoma, including hepatocellular carcinoma, are not associated with aberrant editing of the mRNAs encoding APOB, novel APOBEC1 target 1, or neurofibromin 1. However, more recently, APOBEC1-driven mRNA editing has been shown to be associated with lung adenocarcinoma (9); therefore, the role of aberrant APOBEC1-driven mRNA editing in tumorigenesis requires further clarification.…”

“…Ectopic expression of APOBEC1 occurs in hepatocellular carcinoma (8), lung carcinoma (9), carcinoma in situ cells of the adult testis (10), and contused rat spinal cords (11). A consensus p53 response element in the APOBEC1 promoter can drive expression of the gene in non-intestinal cell types.…”