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

Oncogene volume 34, pages 94–103 (2015)Cite this article

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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 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 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.

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Acknowledgements

PNV is a Banting Postdoctoral Fellow supported by the Canadian Institutes of Health Research. MMW is funded by a Baxter Foundation Scholar Award and C-HC is supported by a Stanford Dean’s Fellowship. We thank Julien Sage for SCLC samples. This work was supported by grant R01 DK078424 (MAK).

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Authors and Affiliations

  1. Department of Pediatrics, Stanford University, Stanford, CA, USA

    P N Valdmanis, B Roy-Chaudhuri, H K Kim, K Chu, Y Zhang, E A Sweet-Cordero & M A Kay

  2. Department of Genetics, Stanford University, Stanford, CA, USA

    P N Valdmanis, B Roy-Chaudhuri, H K Kim, C-H Chuang, D R Caswell, K Chu, Y Zhang, M M Winslow & M A Kay

  3. Division of Hematology/Oncology, Department of Pediatrics, Stanford University, Stanford, CA, USA

    L C Sayles, Y Zheng & E A Sweet-Cordero

  4. Cancer Biology Program, Stanford University, Stanford, CA, USA

    C-H Chuang, D R Caswell & M M Winslow

  5. Stanford Cancer Institute, Stanford University, Stanford, CA, USA

    C-H Chuang, D R Caswell, M M Winslow & E A Sweet-Cordero

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  1. P N Valdmanis
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Valdmanis, P., Roy-Chaudhuri, B., Kim, H. et al. Upregulation of the microRNA cluster at the Dlk1-Dio3 locus in lung adenocarcinoma. Oncogene 34, 94–103 (2015). https://doi.org/10.1038/onc.2013.523

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