Decoding c-Myc networks of cell cycle and apoptosis regulated genes in a transgenic mouse model of papillary lung adenocarcinomas
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Yari Ciribilli1, Prashant Singh2, Reinhard Spanel2,3, Alberto Inga1, Jürgen Borlak2
1Centre for Integrative Biology (CIBIO), University of Trento, 38123 Mattarello, Italy
2Centre for Pharmacology and Toxicology, Hannover Medical School, 30625 Hannover, Germany
3Institute of Pathology, 41747 Viersen, Germany
Jürgen Borlak, e-mail: Borlak.Juergen@mh-hannover.de
Keywords: c-Myc transgenic mouse model of papillary lung adenocarcinomas, whole genome scans, c-Myc regulatory gene networks, c-Myc regulated cell cycle and apoptotic genes, gene reporter assays
Received: April 02, 2015 Accepted: September 21, 2015 Published: October 02, 2015
The c-Myc gene codes for a basic-helix-loop-helix-leucine zipper transcription factor protein and is reported to be frequently over-expressed in human cancers. Given that c-Myc plays an essential role in neoplastic transformation we wished to define its activity in lung cancer and therefore studied its targeted expression to respiratory epithelium in a transgenic mouse disease model. Using histological well-defined tumors, transcriptome analysis identified novel c-Myc responsive cell cycle and apoptosis genes that were validated as direct c-Myc targets using EMSA, Western blotting, gene reporter and ChIP assays.
Through computational analyses c-Myc cooperating transcription factors emerged for repressed and up-regulated genes in cancer samples, namely Klf7, Gata3, Sox18, p53 and Elf5 and Cebpα, respectively. Conversely, at promoters of genes regulated in transgenic but non-carcinomatous lung tissue enriched binding sites for c-Myc, Hbp1, Hif1 were observed. Bioinformatic analysis of tumor transcriptomic data revealed regulatory gene networks and highlighted mortalin and moesin as master regulators while gene reporter and ChIP assays in the H1299 lung cancer cell line as well as cross-examination of published ChIP-sequence data of 7 human and 2 mouse cell lines provided strong evidence for the identified genes to be c-Myc targets. The clinical significance of findings was established by evaluating expression of orthologous proteins in human lung cancer. Taken collectively, a molecular circuit for c-Myc-dependent cellular transformation was identified and the network analysis broadened the perspective for molecularly targeted therapies.
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