Abstract
The aim of the present study was to investigate the aberrant methylation and altered expression of the interferon regulatory factor 8 (IRF8) gene in non-small cell lung cancer (NSCLC). Pyrosequencing assays were performed on 191 tumor specimens from NSCLC patients. The changes in IRF8 mRNA expression, prior to and following treatment with a demethylating agent and methylation itself, were examined in 13 lung cancer cell lines by quantitative polymerase chain reaction (qPCR) and pyrosequencing. IRF8 protein expression was examined in 94 of the 191 NSCLC specimens by immunohistochemical analysis. The IRF8 methylation level was significantly higher in the tumor tissues than in matched non-malignant lung tissues (P<0.0001). IRF8 was more frequently methylated in tumor tissues compared with matched non-malignant lung tissues, as defined by a predetermined cut-off value (P<0.0001). The IRF8 methylation level was strongly correlated with the change in mRNA expression in lung cancer cell lines and with the protein expression level in primary tumors. The IRF8 gene was more frequently methylated in patients without an epidermal growth factor receptor (EGFR) mutation than in patients with an EGFR mutation (P=0.015). IRF8 methylation correlated with recurrent prognosis in adenocarcinomas (log-rank test, P=0.048). IRF8 protein expression was frequently silenced in males, smokers, patients with non-adenocarcinoma or with wild-type EGFR, or in an advanced stage. IRF8 is often silenced by its methylation, which is a frequent event in NSCLC and, therefore, methylation of IRF8 may act as a prognostic marker for recurrence. Analysis of IRF8 methylation status may provide novel opportunities for improved prognosis and therapy of resected NSCLC.
Highlights
Lung cancer is widely prevalent and is one of the leading causes of cancer‐related mortality worldwide
The data indicated that aberrant methylation was a tumor‐specific event in non‐small cell lung cancer (NSCLC)
Comparisons of tumor tissues with matched non‐malignant lung tissues indicated that aberrant methylation of Interferon regulatory factor 8 (IRF8) gene was a tumor‐specific event (Fisher's exact probability test; P
Summary
Lung cancer is widely prevalent and is one of the leading causes of cancer‐related mortality worldwide. The silencing of tumor suppressor genes is frequently caused by epigenetic changes rather than mutations These changes are important in lung cancer, as aberrant methylation of tumor suppressor genes is considered to be one of the contributing factors to the carcinogenesis of non‐small cell lung cancer (NSCLC) [2]. Interferon regulatory factor 8 (IRF8), known as interferon consensus sequence‐binding protein, is a transcription factor belonging to the interferon regulatory factor family It is induced by interferon gamma [3] and is an important regulator of immunity and other physiological processes, including oncogenesis [4]. Repression of IRF8 by aberrant methylation is a molecular determinant of apoptotic resistance and the metastatic phenotype in human metastatic colon carcinoma cell lines and murine mammary carcinoma with lung metastasis [3]. Aberrant methylation of the IRF8 gene in nasopharyngeal, esophageal and multiple other carcinomas has been reported [11]
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