Frequent downregulation of the transcription factor Foxa2 in lung cancer through epigenetic silencing
| Autor: | David A. Gonzalez, Francesco D'Alo', Ester C. Löwenberg, Balazs Halmos, Daniel B. Costa, William G. Richards, Matthew Meyerson, Daniel G. Tenen, Beow Y. Yeap, Tajhal Dayaram, Hiroyuki Yasuda, John J. Godleski, Daniela S. Basseres, Olivier Kocher, Susumu Kobayashi |
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| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Pulmonary and Respiratory Medicine
Male Cancer Research Lung Neoplasms DNA Mutational Analysis Gene Dosage Down-Regulation Gene Expression Kaplan-Meier Estimate MUTAÇÃO Biology Adenocarcinoma Article Epigenesis Genetic Downregulation and upregulation Carcinoma Non-Small-Cell Lung Cell Line Tumor Gene expression medicine Humans Epigenetics Lung cancer Promoter Regions Genetic Transcription factor reproductive and urinary physiology Settore MED/06 - ONCOLOGIA MEDICA Lung Cancer Epigenetic Promoter respiratory system DNA Methylation Middle Aged medicine.disease Molecular biology respiratory tract diseases Gene Expression Regulation Neoplastic Oncology embryonic structures DNA methylation Cancer research Hepatocyte Nuclear Factor 3-beta Female |
| Zdroj: | Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual) Universidade de São Paulo (USP) instacron:USP |
| Popis: | We sought to determine the mechanisms of downregulation of the airway transcription factor Foxa2 in lung cancer and the expression status of Foxa2 in non-small-cell lung cancer (NSCLC).A series of 25 lung cancer cell lines were evaluated for Foxa2 protein expression, FOXA2 mRNA levels, FOXA2 mutations, FOXA2 copy number changes and for evidence of FOXA2 promoter hypermethylation. In addition, 32 NSCLCs were sequenced for FOXA2 mutations and 173 primary NSCLC tumors evaluated for Foxa2 expression using an immunohistochemical assay.Out of the 25 cell lines, 13 (52%) had undetectable FOXA2 mRNA. The expression of FOXA2 mRNA and Foxa2 protein were congruent in 19/22 cells (p = 0.001). FOXA2 mutations were not identified in primary NSCLCs and were infrequent in cell lines. Focal or broad chromosomal deletions involving FOXA2 were not present. The promoter region of FOXA2 had evidence of hypermethylation, with an inverse correlation between FOXA2 mRNA expression and presence of CpG dinucleotide methylation (p0.0001). In primary NSCLC tumor specimens, there was a high frequency of either absence (42/173, 24.2%) or no/low expression (96/173, 55.4%) of Foxa2. In 130 patients with stage I NSCLC there was a trend towards decreased survival in tumors with no/low expression of Foxa2 (HR of 1.6, 95%CI 0.9-3.1; p = 0.122).Loss of expression of Foxa2 is frequent in lung cancer cell lines and NSCLCs. The main mechanism of downregulation of Foxa2 is epigenetic silencing through promoter hypermethylation. Further elucidation of the involvement of Foxa2 and other airway transcription factors in the pathogenesis of lung cancer may identify novel therapeutic targets. |
| Databáze: | OpenAIRE |
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