Abstract
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.
Highlights
The molecular functions of the c-Myc oncogene have been studied in considerable detail and the seminal review of Dang [1] highlights its involvement in many biological pathways associated with neoplastic transformation, cell growth and proliferation
In an effort to define genetic events associated with c-Myc transforming capacity in lung cancer a transgenic disease model of non-small cell lung cancer (NSCLC)/papillary adenocarcinomas was studied and we focused on cell cycle and apoptosis regulated genes in response to oncogenic c-Myc signaling
Expression of the transcription factor Dp1 (Tfdp1), i.e. a heterodimeric partner of E2Fs was significantly increased and the findings suggest c-Myc to abrogate the Rb protein/E2F regulatory pathway in the control of G1 cell cycle progression
Summary
The molecular functions of the c-Myc oncogene have been studied in considerable detail and the seminal review of Dang [1] highlights its involvement in many biological pathways associated with neoplastic transformation, cell growth and proliferation. It was demonstrated that c-Myc cooperates with mutation-activated BRAFV600E during mouse lung cancer development by suppressing senescence [15] and was shown to promote tumor aggressiveness in non-small cell lung cancer through suppression of miRNA-29b [16]. C-Myc is frequently elevated in tumors and genetic alterations such as translocations, gene amplifications and mutations in regulators of c-myc expression directly affect c-Myc activity, the molecular pathology of organ specific tumors differ to suggest cell type and tissue specific gene regulatory networks. In an effort to define genetic events associated with c-Myc transforming capacity in lung cancer a transgenic disease model of NSCLC/papillary adenocarcinomas was studied and we focused on cell cycle and apoptosis regulated genes in response to oncogenic c-Myc signaling
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