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Differential gene expression profiles of radioresistant oesophageal cancer cell lines established by continuous fractionated irradiation.

ABSTRACT: Radiation therapy is a powerful tool for the treatment of oesophageal cancer. We established radioresistant cell lines by applying fractionated irradiation in order to identify differentially expressed genes between parent and radioresistant cells. Six oesophageal cancer cell lines (TE-2, TE-5, TE-9, TE-13, KYSE170, and KYSE180) were treated with continuous 2 Gy fractionated irradiation (total dose 60 Gy). We compared expression profiles of each parent and radioresistant lines on a cDNA microarray consisting of 21168 genes. In the fractionated irradiation trial, four radioresistant sublines (TE-2R, TE-9R, TE-13R, KYSE170R) were established successfully, and we identified 19 upregulated and 28 downregulated genes common to radioresistant sublines. Upregulated genes were associated with apoptosis and inflammatory response (BIRC2 and COX-2), DNA metabolism (CD73), and cell growth (PLAU). Downregulated genes were associated with apoptosis (CASP6), cell adhesion (CDH1 and CDH3), transcription (MLL3), and cell cycle (CDK6). Some of these genes were known to be associated with radiation response, such as COX-2, but others were novel. Reverse transcription-polymerase chain reaction confirmed that genes selected by cDNA microarray were overexpressed in clinical specimens of radioresistant cases. Global gene analysis of radioresistant sublines may provide new insight into mechanisms of radioresistance and effective radiation therapy.

SUBMITTER: Fukuda K

PROVIDER: S-EPMC2409931 | biostudies-literature | 2004 Oct

REPOSITORIES: biostudies-literature

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Differential gene expression profiles of radioresistant oesophageal cancer cell lines established by continuous fractionated irradiation.

Fukuda K K Sakakura C C Miyagawa K K Kuriu Y Y Kin S S Nakase Y Y Hagiwara A A Mitsufuji S S Okazaki Y Y Hayashizaki Y Y Yamagishi H H

British journal of cancer 20041001 8

Radiation therapy is a powerful tool for the treatment of oesophageal cancer. We established radioresistant cell lines by applying fractionated irradiation in order to identify differentially expressed genes between parent and radioresistant cells. Six oesophageal cancer cell lines (TE-2, TE-5, TE-9, TE-13, KYSE170, and KYSE180) were treated with continuous 2 Gy fractionated irradiation (total dose 60 Gy). We compared expression profiles of each parent and radioresistant lines on a cDNA microarr ...[more]

PMID: 15365572

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Project description:BackgroundThe purpose of this study was to identify miRNAs and genes involved in nasopharyngeal carcinoma (NPC) radioresistance, and explore the underlying mechanisms in the development of radioresistance.MethodsWe used microarrays to compare the differences of both miRNA and mRNA expression profiles in the radioresistant NPC CNE2-IR and radiosensitive NPC CNE2 cells, applied qRT-PCR to confirm the reliability of microarray data, adopted databases prediction and anticorrelated analysis of miRNA and mRNA expression to identify the miRNA target genes, and employed bioinformatics tools to examine the functions and pathways in which miRNA target genes are involved, and construct a miRNA-target gene regulatory network. We further investigated the roles of miRNA-23a and its target gene IL-8 in the NPC radioresistance.ResultsTHE MAIN FINDINGS WERE FOURFOLD: (1) fifteen differential miRNAs and 372 differential mRNAs were identified, and the reliability of microarray data was validated for randomly selected eight miRNAs and nine genes; (2) 174 miRNA target were identified, and most of their functions and regulating pathways were related to tumor therapeutic resistance; (3) a posttranscriptional regulatory network including 375 miRNA-target gene pairs was constructed, in which the ten genes were coregulated by the six miRNAs; (4) IL-8 was a direct target of miRNA-23a, the expression levels of IL-8 were elevated in the radioresistant NPC tissues and showed inverse correlation with miRNA-23a expression, and genetic upregulation of miRNA-23a and antibody neutralization of secretory IL-8 could reduce NPC cells radioresistance.ConclusionsWe identified fifteen differential miRNAs and 372 differential mRNAs in the radioresistant NPC cells, constructed a posttranscriptional regulatory network including 375 miRNA-target gene pairs, discovered the ten target genes coregulated by the six miRNAs, and validated that downregulated miRNA-23a was involved in NPC radioresistance through directly targeting IL-8. Our data form a basis for further investigating the mechanisms of NPC radioresistance.

Project description:Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, irreversible lung disorder of unknown cause. This disease is characterized by profibrotic activation of resident pulmonary fibroblasts resulting in aberrant deposition of extracellular matrix (ECM) proteins. However, although much is known about the pathophysiology of IPF, the cellular and molecular processes that occur and allow aberrant fibroblast activation remain an unmet need. To explore the differentially expressed proteins (DEPs) associated with aberrant activation of these fibroblasts, we used the IPF lung fibroblast cell lines LL97A (IPF-1) and LL29 (IPF-2), compared to the normal lung fibroblast cell line CCD19Lu (NL-1). Protein samples were quantified and identified using a label-free quantitative proteomic analysis approach by liquid chromatography-tandem mass spectrometry (LC-MS/MS). DEPs were identified after pairwise comparison, including all experimental groups. Gene Ontology (GO) enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG), and Protein-Protein Interaction (PPI) network construction were used to interpret the proteomic data. Eighty proteins expressed exclusively in the IPF-1 and IPF-2 clusters were identified. In addition, 19 proteins were identified up-regulated in IPF-1 and 10 in IPF-2; 10 proteins were down-regulated in IPF-1 and 2 in IPF-2 when compared to the NL-1 proteome. Using the search tool for retrieval of interacting genes/proteins (STRING) software, a PPI network was constructed between the DEPs and the 80 proteins expressed exclusively in the IPF-2 and IPF-1 clusters, containing 115 nodes and 136 edges. The 10 hub proteins present in the IPP network were identified using the CytoHubba plugin of the Cytoscape software. GO and KEGG pathway analyses showed that the hub proteins were mainly related to cell adhesion, integrin binding, and hematopoietic cell lineage. Our results provide relevant information on DEPs present in IPF lung fibroblast cell lines when compared to the normal lung fibroblast cell line that could play a key role during IPF pathogenesis.

Project description:BackgroundMicroRNAs (miRNAs), a group of short non-coding RNAs that negatively regulate gene expression, have recently emerged as potential modulators of cellular response to ionizing radiations both in vitro and in vivo in various cell types and tissues. However, in epidermal cells, the involvement of the miRNA machinery in the cellular response to ionizing radiations remains to be clarified. Indeed, understanding the mechanisms of cutaneous radiosensitivity is an important issue since skin is the most exposed organ to ionizing radiations and among the most sensitive.ResultsWe settled up an expression study of miRNAs in primary human skin keratinocytes using a microfluidic system of qPCR assay, which permits to assess the expression of almost 700 annotated miRNAs. The keratinocytes were cultured to a proliferative or a differentiated state mimicking basal or suprabasal layers of human epidermis. These cells were irradiated at 10 mGy or 6 Gy and RNA was extracted 3 hours after irradiation. We found that proliferative cells irradiated at 6 Gy display a global fall of miRNA expression whereas differentiated cells exposed to the same dose display a global increase of miRNAs expression. We identified twenty miRNAs weakly but significantly modulated after 6 Gy irradiation, whereas only 2 miRNAs were modulated after low-dose irradiation in proliferating cells. To go further into the biological meaning of this miRNA response, we over-expressed some of the responding miRNA in proliferating cells: we observed a significant decrease of cell viability 72 hours after irradiation. Functional annotation of their predicted targets revealed that G-protein related pathways might be regulated by these responding miRNAs.ConclusionsOur results reveal that human primary keratinocytes exposed to ionizing irradiation expressed a miRNA pattern strongly related to the differentiation status of irradiated cells. We also demonstrate that some miRNAs play a role in the radiation response to ensure the short-term survival of irradiated keratinocytes.

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Differential gene expression profiles of radioresistant oesophageal cancer cell lines established by continuous fractionated irradiation.

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Differential gene expression profiles of radioresistant oesophageal cancer cell lines established by continuous fractionated irradiation.

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