Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Global Differential Gene Expression Analysis of Spontaneous Lung Tumors in B6C3F1 Mice: Comparison to Human Non-Small Cell Lung Cancer

ABSTRACT: Introduction: Lung cancer is the leading cause of cancer-related death in people. There are several chemically induced and genetically modified mouse models used to study lung cancer. We hypothesized that spontaneous murine (B6C3F1) lung tumors can serve as a model to study human non-small cell lung cancer (NSCLC). Methods: RNA was extracted from untreated 2-year-old B6C3F1 mouse spontaneous lung (SL) tumors and age-matched normal lung tissue from a chronic inhalation NTP study. Global gene expression analysis was performed using Affymetrix Mouse Genome 430 2.0 GeneChip® arrays. After data normalization, for each probe set, pairwise comparisons between groups were made using a bootstrap t-test while controlling the mixed directional false discovery rate (mdFDR) to generate a differential gene expression list. IPA, KEGG, and EASE software tools were used to evaluate the overrepresented cancer genes and pathways. Results: MAPK and TGF-beta pathways were overrepresented within the dataset. Almost all of the validated genes by quantitative real time RT-PCR had comparable directional fold changes with the microarray data. The candidate oncogenes included Kras, Braf, Raf1, Id2, Hmga1, Cks1b, and Foxf1. The candidate tumor suppressor genes included Rb1, Cdkn2a, Hnf4a, Tcf21, Ptprd, Hpgd, Hopx, Ogn, Id4, Hoxa5, Smad6, Smad7, Zbtb16, Cyr61, Dusp4, and Ifi16. In addition, several genes important in lung development were also differentially expressed, such as Smad6, Hopx, Sox4, Sox9 and Mycn. Conclusion: In this study, we have demonstrated that several cancer genes and signaling pathways relevant for human NSCLC were similarly altered in spontaneous murine lung tumors. Six spontaneous lung tumors and six normal lungs (as controls) from 2-year-old B6C3F1 mice.

ORGANISM(S): Mus musculus

SUBMITTER: NIEHS Microarray Core

PROVIDER: E-GEOD-31013 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Differential transcriptomic analysis of spontaneous lung tumors in B6C3F1 mice: comparison to human non-small cell lung cancer.

Pandiri Arun R AR Sills Robert C RC Ziglioli Vincent V Ton Thai-Vu T TV Hong Hue-Hua L HH Lahousse Stephanie A SA Gerrish Kevin E KE Auerbach Scott S SS Shockley Keith R KR Bushel Pierre R PR Peddada Shyamal D SD Hoenerhoff Mark J MJ

Toxicologic pathology 20120611 8

Lung cancer is the leading cause of cancer-related death in people and is mainly due to environmental factors such as smoking and radon. The National Toxicology Program (NTP) tests various chemicals and mixtures for their carcinogenic hazard potential. In the NTP chronic bioassay using B6C3F1 mice, the incidence of lung tumors in treated and control animals is second only to the liver tumors. In order to study the molecular mechanisms of chemically induced lung tumors, an understanding of the ge ...[more]

PMID: 22688403

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Project description:Lung cancer is the leading cause of cancer death in the United States. Among the various subtypes of lung cancers, pulmonary neuroendocrine (NE) cancer, including small cell lung cancer (SCLC) and NE-non-small cell lung cancer (NE-NSCLC), is a particularly aggressive malignancy that is distinct from classic non–small cell lung cancer (NSCLC) in its metastatic potential and treatment response. Recently, the lineage-specific transcription factors Achaete-scute homolog 1 (ASCL1), NEUROD1, and POU2F3 have been reported to identify heterogeneity in pulmonary NE cancers. These transcription factors bind different genomic loci to regulate distinct gene programs in pulmonary NE cancers. However, the signaling pathways downstream of these transcription factors that distinguish these pulmonary NE cancer subtypes are not well characterized. Regulated protein secretion is critically involved in cell signaling and cell-cell communication events, and is known to be a hallmark associated with pulmonary NE tumors. Using a large-scale mass spectrometric approach, we performed quantitative secretomic analysis 13 cell lines including a pair of isogenic cell lines, i.e., an immortalized human bronchial epithelial cell and an ASCL1high NE NSCLC line. This panel also contained 6 additional ASCL1High and 5 NEUROD1High NE-lung cancer cell lines. From the conditioned media of the 13 cell lines, we identified and quantified 1,626 proteins. The NE-specific secretome is associated with a number of biological processes related to neurodevelopment. Further analysis of the upregulated proteins in ASCL1High subtype NE-lung cancer cells leads to the identification of IGFBP5 being a specific secreted marker for ASCL1High pulmonary NE cancer cells. Furthermore, IGFBP5 is also upregulated in the serum of a genetically modified mouse model of ASCL1High SCLC, as well as in human ASCL1High SCLC tumors. Mechanistically, ASCL1 binds to E-box elements in the IGFBP5 gene and directly regulates its transcription. Knockdown of ASCL1 in SCLC decreases IGFBP5 expression, which, in turn, leads to hyperactivation of the IGF-1R pathway. Pharmacological co-targeting of ASCL1 and IGF-1R signaling results in markedly synergistic, growth inhibitory effects in ASCL1High SCLC both in vitro and in vivo. Together, our quantitative proteomic analysis identifies a novel secreted marker and a new combination therapy for ASCL1High pulmonary NE cancer cells. In addition, we expect that the data sets will serve as an invaluable resource, providing the foundation for future mechanistic studies and biomarker discovery that helps delineate the molecular underpinnings of pulmonary NE tumors.

Dataset Information

Global Differential Gene Expression Analysis of Spontaneous Lung Tumors in B6C3F1 Mice: Comparison to Human Non-Small Cell Lung Cancer

Publications

Differential transcriptomic analysis of spontaneous lung tumors in B6C3F1 mice: comparison to human non-small cell lung cancer.

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