title: 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 Kras(G12D) 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 Kras(G12D) 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 single-nucleotide polymorphisms 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 markedly 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 Kras(G12D) 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.
authors: 1] Department of Pediatrics, Stanford University, Stanford, CA, USA [2] Department of Genetics, Stanford University, Stanford, CA, USA.
authors: P N
authors: PN
authors: Valdmanis
authors: 1] Department of Pediatrics, Stanford University, Stanford, CA, USA [2] Department of Genetics, Stanford University, Stanford, CA, USA.
authors: B
authors: B
authors: Roy-Chaudhuri
authors: 1] Department of Pediatrics, Stanford University, Stanford, CA, USA [2] Department of Genetics, Stanford University, Stanford, CA, USA.
authors: H K
authors: HK
authors: Kim
authors: Division of Hematology/Oncology, Department of Pediatrics, Stanford University, Stanford, CA, USA.
authors: L C
authors: LC
authors: Sayles
authors: Division of Hematology/Oncology, Department of Pediatrics, Stanford University, Stanford, CA, USA.
authors: Y
authors: Y
authors: Zheng
authors: 1] Department of Genetics, Stanford University, Stanford, CA, USA [2] Cancer Biology Program, Stanford University, Stanford, CA, USA [3] Stanford Cancer Institute, Stanford University, Stanford, CA, USA.
authors: C-H
authors: CH
authors: Chuang
authors: 1] Department of Genetics, Stanford University, Stanford, CA, USA [2] Cancer Biology Program, Stanford University, Stanford, CA, USA [3] Stanford Cancer Institute, Stanford University, Stanford, CA, USA.
authors: D R
authors: DR
authors: Caswell
authors: 1] Department of Pediatrics, Stanford University, Stanford, CA, USA [2] Department of Genetics, Stanford University, Stanford, CA, USA.
authors: K
authors: K
authors: Chu
authors: 1] Department of Pediatrics, Stanford University, Stanford, CA, USA [2] Department of Genetics, Stanford University, Stanford, CA, USA.
authors: Y
authors: Y
authors: Zhang
authors: 1] Department of Genetics, Stanford University, Stanford, CA, USA [2] Cancer Biology Program, Stanford University, Stanford, CA, USA [3] Stanford Cancer Institute, Stanford University, Stanford, CA, USA.
authors: M M
authors: MM
authors: Winslow
authors: 1] Department of Pediatrics, Stanford University, Stanford, CA, USA [2] Division of Hematology/Oncology, Department of Pediatrics, Stanford University, Stanford, CA, USA [3] Stanford Cancer Institute, Stanford University, Stanford, CA, USA.
authors: E A
authors: EA
authors: Sweet-Cordero
authors: 1] Department of Pediatrics, Stanford University, Stanford, CA, USA [2] Department of Genetics, Stanford University, Stanford, CA, USA.
authors: M A
authors: MA
authors: Kay
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism*; D000483:Alleles; D000818:Animals; D002135:Calcium-Binding Proteins; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism; D045744:Cell Line, Tumor; D002874:Chromosome Mapping; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D007453:Iodide Peroxidase / Q000235:genetics* / Q000378:metabolism; D019656:Loss of Heterozygosity; D008175:Lung Neoplasms / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D005810:Multigene Family; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D012313:RNA / Q000378:metabolism; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D002135:Calcium-Binding Proteins; C497868:Cd22 protein, mouse; C512941:DLK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D035683:MicroRNAs; D051918:Sialic Acid Binding Ig-like Lectin 2; D012313:RNA; C117274:iodothyronine deiodinase type III; D007453:Iodide Peroxidase