Abstract
Mouse models of cancer play an important role in elucidating the molecular mechanisms that contribute to tumorigenesis. The extent to which these models resemble one another and their human counterparts at the molecular level is critical in understanding tumorigenesis. In this study, we carried out a comparative gene expression analysis to generate a detailed molecular portrait of a transgenic mouse model of IGFIR-driven lung cancer. IGFIR-driven tumors displayed a strong resemblance with established mouse models of lung adenocarcinoma, particularly EGFR-driven models highlighted by elevated levels of the EGFR ligands Ereg and Areg. Cross-species analysis revealed a shared increase in human lung adenocarcinoma markers including Nkx2.1 and Napsa as well as alterations in a subset of genes with oncogenic and tumor suppressive properties such as Aurka, Ret, Klf4 and Lats2. Integrated miRNA and mRNA analysis in IGFIR-driven tumors identified interaction pairs with roles in ErbB signaling while cross-species analysis revealed coordinated expression of a subset of conserved miRNAs and their targets including miR-21-5p (Reck, Timp3 and Tgfbr3). Overall, these findings support the use of SPC-IGFIR mice as a model of human lung adenocarcinoma and provide a comprehensive knowledge base to dissect the molecular pathogenesis of tumor initiation and progression.
Highlights
Lung cancer is the leading cause of cancer-related deaths worldwide [1]
To characterize IGFIR-driven lung tumorigenesis at the gene expression level, RNA-Seq was carried out on tumors from surfactant protein-C (SPC)-IGFIR transgenic mice and normal lung tissue obtained from non-transgenic animals (Fig 1A)
Top up-regulated genes included the IGFIR/IR adaptor Grb14, the serine-threonine kinase Stk39 and the EGFR ligands Ereg and Areg while the most significantly down-regulated genes included those expressed in normal lung cell populations including Rspo4, Myl3 and Reg3g
Summary
Non-small cell lung cancer (NSCLC) represents the major form of the disease accounting for up to 85% of cases and can be broadly categorized into adenocarcinoma (ADC), squamous cell carcinoma (SCC) and large cell carcinoma (LLC) histological subtypes [2,3]. ADC is the most frequently diagnosed form of NSCLC and is characterized by glandular differentiation, expression of thyroid transcription factor 1 (TTF1 known as NK2 homeobox 1 or NKX2-1) and frequent mutations in KRAS or EGFR [2,3]. SCC accounts for approximately 40% of NSCLC cases and can be distinguished from ADC by expression of p63 and basal keratins while LLC is less prevalent and diagnosed when features of ADC or SCC are absent [2,3].
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