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MRNA expression levels and genetic status of genes involved in the EGFR and NF-?B pathways in metastatic non-small-cell lung cancer patients.

ABSTRACT: BACKGROUND: Metastatic non-small-cell lung cancer (NSCLC) has a dismal prognosis. EGFR is overexpressed or mutated in a large proportion of cases. Downstream components of the EGFR pathway and crosstalk with the NF-?B pathway have not been examined at the clinical level. We explored the prognostic significance of the mRNA expression of nine genes in the EGFR and NF-?B pathways and of BRCA1 and RAP80 in patients in whom EGFR and K-ras gene status had previously been determined. In addition, NFKBIA and DUSP22 gene status was also determined. METHODS: mRNA expression of the eleven genes was determined by QPCR in 60 metastatic NSCLC patients and in nine lung cancer cell lines. Exon 3 of NFKBIA and exon 6 of DUSP22 were analyzed by direct sequencing. Results were correlated with outcome to platinum-based chemotherapy in patients with wild-type EGFR and to erlotinib in those with EGFR mutations. RESULTS: BRCA1 mRNA expression was correlated with EZH2, AEG-1, Musashi-2, CYLD and TRAF6 expression. In patients with low levels of both BRCA1 and AEG-1, PFS was 13.02 months, compared to 5.4 months in those with high levels of both genes and 7.7 months for those with other combinations (P=0.025). The multivariate analysis for PFS confirmed the prognostic role of high BRCA1/AEG-1 expression (HR, 3.1; P=0.01). Neither NFKBIA nor DUSP22 mutations were found in any of the tumour samples or cell lines. CONCLUSIONS: The present study provides a better understanding of the behaviour of metastatic NSCLC and identifies the combination of BRCA1 and AEG-1 expression as a potential prognostic model.

SUBMITTER: Santarpia M

PROVIDER: S-EPMC3203857 | biostudies-other | 2011

REPOSITORIES: biostudies-other

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mRNA expression levels and genetic status of genes involved in the EGFR and NF-κB pathways in metastatic non-small-cell lung cancer patients.

Santarpia Mariacarmela M Magri Ignacio I Sanchez-Ronco Maria M Costa Carlota C Molina-Vila Miguel Angel MA Gimenez-Capitan Ana A Bertran-Alamillo Jordi J Mayo Clara C Benlloch Susana S Viteri Santiago S Gasco Amaya A Mederos Nuria N Carcereny Enric E Taron Miquel M Rosell Rafael R

Journal of translational medicine 20110927

<h4>Background</h4>Metastatic non-small-cell lung cancer (NSCLC) has a dismal prognosis. EGFR is overexpressed or mutated in a large proportion of cases. Downstream components of the EGFR pathway and crosstalk with the NF-κB pathway have not been examined at the clinical level. We explored the prognostic significance of the mRNA expression of nine genes in the EGFR and NF-κB pathways and of BRCA1 and RAP80 in patients in whom EGFR and K-ras gene status had previously been determined. In addition ...[more]

PMID: 21951562

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Project description:Objectives: Epidermal growth factor receptor-tyrosine kinase inhibitors are widely used for lung epidermal growth factor receptor-positive lung adenocarcinomas, but acquired resistance is inevitable. Although non-coding RNAs, such as circular RNA and microRNA, are known to play vital roles in epidermal growth factor receptor-tyrosine kinase inhibitor resistance, comprehensive analysis is lacking. Thus, this study aimed to explore the circular RNA-microRNA-messenger RNA regulatory network involved in epidermal growth factor receptor-tyrosine kinase inhibitor resistance. Methods: To identify differentially expressed genes between the epidermal growth factor receptor-tyrosine kinase inhibitor sensitive cell line PC9 and resistant cell line PC9/ epidermal growth factor receptor-tyrosine kinase inhibitor resistance(PC9/ER), circular RNA, microRNA and messenger RNA microarrays were performed. Candidates were then identified to construct a circular RNA-microRNA-messenger RNA network using bioinformatics. Additionally, Gene Oncology and Kyoto Encyclopedia of Genes and Genomes pathway analyses were conducted to evaluate the network messenger RNA, setting up a protein-protein interaction network for hub-gene identification. Afterwards, RNA immunoprecipitation was performed to enrich microRNA, and quantitative real-time PCR was used to estimated gene expression levels. Results: In total, 603, 377, and 1863 differentially expressed circular RNA, microRNA, messenger RNAs, respectively, were identified using microarray analysis, constructing a circular RNA-microRNA-messenger RNA network containing 18 circular RNAs, 17 microRNAs and 175 messenger RNAs. Moreover, Gene Oncology and Kyoto Encyclopedia of Genes and Genomes pathway analyses showed that the most enriched biological process terms and pathways were related to epidermal growth factor receptor-tyrosine kinase inhibitor resistance, including Wnt and Hippo signaling pathways. Based on the competing endogenous RNA and protein-protein interaction network, circ-0007312 was showed to interact with miR-764 and both circ-0003748 and circ-0001398 were shown to interact with miR-628; both these microRNAs targeted MAPK1. Furthermore, circ-0007312, circ-0003748, circ-0001398, and MAPK1 were up-regulated, whereas miR-764 and miR-628 were downregulated in PC9/ER cells as compared to parental PC9 cells. We also found that circ-0007312 and miR-764 were positively expressed in plasma. Conclusions: Our original study associated with mechanism of target therapy in lung cancer provided a systematic and comprehensive regulation of circular RNA, microRNA and messenger RNA in epidermal growth factor receptor-tyrosine kinase inhibitor resistance. It was found that circ-0007312- miR-764-MAPK1, circ-0003748-miR-628-MAPK1, and circ-0001398-miR-628-MAPK1 axis may play key roles in epidermal growth factor receptor-tyrosine kinase inhibitor resistance.

Project description:BackgroundFive hundred 8-d old male broilers Cobb500 were randomly allotted into 10 treatments in factorial arrangement with 5 Cu levels (0, 4, 8, 12, and 16 mg/kg), and 2 sources (Cu proteinate, CuPro and Cu sulphate, CuSO4.5H2O) for a 10-d-experiment.ResultsFeed conversion ratio (FCR) was better (P < 0.05) in CuPro fed chicks compared with CuSO4.5H2O group. Average daily feed intake (ADFI) decreased linearly (P < 0.05) as dietary Cu increased. A quadratic response (P < 0.05) to Cu levels was found for FCR, being optimized at 9.87 and 8.84 mg Cu/kg in CuPro and CuSO4.5H2O diets, respectively. Copper supplementation linearly increased liver Cu content (P < 0.05) and tended to linearly increase (P = 0.07) phosphorus (P) and copper in tibia. Manganese and zinc were higher (P < 0.05) in tibia of CuPro fed birds. Broilers fed CuPro exhibited lower liver iron (P < 0.05) content, lower activities of Cu, Zn superoxide dismutase (CuZnSOD) in breast muscle and liver, and glutathione peroxidase in liver. Glutathione peroxidase reduced linearly (P < 0.05) with CuPro levels and increased linearly (P < 0.05) with CuSO4.5H2O levels and were lower (P < 0.05) in all CuPro levels in breast muscle. Breast muscle malondialdehyde concentration tended to be higher (P = 0.08) in broilers fed CuSO4.5H2O. Copper levels linearly increased (P < 0.05) metallothionein (MT) and malate dehydrogenase (MDH) expression in liver, and six-transmembrane epithelial antigen of the prostate-1 (STEAP-1) in the intestine. Copper elicited a quadratic response (P < 0.050) in AKT-1 and mammalian target of rapamycin (mTOR) in breast muscle, CuZnSOD in liver and antioxidant 1 copper chaperone (ATOX 1) in intestine. Broilers fed CuPro exhibited higher mRNA expression of mTOR in muscle breast and lower CuZnSOD in liver and ATOX 1 in intestine. Interaction (P < 0.05) between levels and sources was found in mRNA expression for GSK-3β, MT, and CuZnSOD in breast muscle, FAS and LPL in liver and MT and CTR1 in intestine.ConclusionsCuPro showed beneficial effects on feed conversion and bone mineralization. Organic and inorganic Cu requirements are 9.87 and 8.84 mg Cu/kg, respectively.

Dataset Information

MRNA expression levels and genetic status of genes involved in the EGFR and NF-?B pathways in metastatic non-small-cell lung cancer patients.

Publications

mRNA expression levels and genetic status of genes involved in the EGFR and NF-κB pathways in metastatic non-small-cell lung cancer patients.

Similar Datasets

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