Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Gene expression in hypoxic non-small cell lung cancer

ABSTRACT: Hypoxia triggers aggressive cancer growth and contributes to chemotherapy resistance. Novel therapeutic strategies aim at targeting hypoxia activated signaling pathways. Tumor hypoxia not only affects neoplastic tumor cells but also the surrounding stroma cells. Therefore, a novel ex vivo model was established, which allows the study of hypoxia effects in fragments of non-small cell lung cancer (NSCLC) with preserved tumor microenvironment and 3D-structure. Microarray analysis identified 107 significantly regulated genes with at least two-fold expression change in hypoxic compared to normoxic fragments. However, only four genes were significantly regulated in both subtypes, adenocarcinoma and squamous cell carcinoma. The hypoxic regulation of these four genes was verified in an independent set using quantitative PCR. Non-small cell lung cancer (NSCLC) fragments were cultured ex vivo under hypoxia or normoxia for three days. cDNA microarray analysis was performed in hypoxic and normoxic lung cancer fragments from ten patients.

ORGANISM(S): Homo sapiens

SUBMITTER: Katharina Leithner

PROVIDER: E-GEOD-30979 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Hypoxia increases membrane metallo-endopeptidase expression in a novel lung cancer ex vivo model - role of tumor stroma cells.

Leithner Katharina K Wohlkoenig Christoph C Stacher Elvira E Lindenmann Jörg J Hofmann Nicole A NA Gallé Birgit B Guelly Christian C Quehenberger Franz F Stiegler Philipp P Smolle-Jüttner Freyja-Maria FM Philipsen Sjaak S Popper Helmut H HH Hrzenjak Andelko A Olschewski Andrea A Olschewski Horst H

BMC cancer 20140125

<h4>Background</h4>Hypoxia-induced genes are potential targets in cancer therapy. Responses to hypoxia have been extensively studied in vitro, however, they may differ in vivo due to the specific tumor microenvironment. In this study gene expression profiles were obtained from fresh human lung cancer tissue fragments cultured ex vivo under different oxygen concentrations in order to study responses to hypoxia in a model that mimics human lung cancer in vivo.<h4>Methods</h4>Non-small cell lung ca ...[more]

PMID: 24460801

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Project description:The activation of the transcription factor Hypoxia-inducible factor-1 (HIF-1) plays an essential role in tumor development, tumor progression and resistance to chemo- and radiotherapy. In order to identify compounds targeting the HIF pathway, a small-molecule library was screened using a luciferase-driven HIF-1 reporter cell line under hypoxia. The high throughput screen led to the identification of a class of aminoalkyl-substituted compounds that inhibited hypoxia-induced HIF-1 target gene expression in human lung cancer cell lines at low nanomolar concentrations but did not affect expression levels of genes outside of the HIF-1 pathway. Lead structure BAY 87-2243 was found to inhibit HIF-1Î± protein accumulation under hypoxic conditions in NSCLC cell line H460 but had no effect on HIF-1Î± protein accumulation and HIF target gene expression in RCC4 cells lacking VHL activity or in H460 cells after inhibition of HIF prolyl hydroxylase activity. BAY 87-2243 had no effect on HIF-Î±-mRNA levels. Antitumor activity of BAY 87-2243 and suppression of HIF-1 target gene expression in vivo was demonstrated in a H460 xenograft model. BAY 87-2243 did not inhibit cell proliferation under standard conditions. However under glucose depletion, a condition favoring mitochondrial ATP generation as energy source, BAY 87-2243 inhibited cell proliferation in the nanomolar range. Further experiments revealed that BAY 87-2243 inhibits mitochondrial production of reactive oxygen species (ROS) by blocking complex I activity but has no effect on complex III activity. Lowering of mitochondrial ROS production to reduce hypoxia-induced HIF-1 activity in tumors might be an interesting therapeutic approach to overcome chemo- and radiotherapy-resistance of hypoxic tumors. We used microarrays to detail the global programme of gene expression that is induced in NSCLC cell line H460 upon hypoxia (16 h incubation at 1 % pO2) and evaluated a dose-dependent effect of our HIF-1-pathway inhibitor BAY 87-2243 on genes tthat are affected by hypoxia. Specificity of BAY 87-2243 for the suppression of HIF-1-mediated gene transcription on a genome-wide scale was evaluated by microarray hybridizations using Affymetrix GeneChip Human Gene 1.0 ST arrays. RNA from normoxic H460 cells and from hypoxic H460 cells incubated with 1, 10 and 100 nM BAY 87-2243 respectively was subjected to array hybridization. Of those 30 genes that were most strongly suppressed by 100 nM BAY 87-2243 in hypoxic H460 cells compared to DMSO-treated hypoxic H460 cells, virtually all of them are induced by prior hypoxia and most of these genes have been described in the literature as HIF-1 target genes

Dataset Information

Gene expression in hypoxic non-small cell lung cancer

Publications

Hypoxia increases membrane metallo-endopeptidase expression in a novel lung cancer ex vivo model - role of tumor stroma cells.

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