Epigenetic activation of hepatocyte growth factor is associated with epithelial-mesenchymal transition and clinical outcome in non-small cell lung cancer

Abstract

Hepatocyte growth factor (HGF) expression is repressed in normal differentiated lung epithelial cells, but its expression is aberrantly upregulated in non-small cell lung cancer (NSCLC) and acts as a poor prognostic factor. The underlying molecular mechanisms of aberrant HGF expression are unclear. In this study, a novel differential methylation region located in the HGF promoter was identified, which was associated with aberrant HGF expression in NSCLC. The correlations of HGF promoter methylation detected by methylation specific PCR and HGF expression detected by immunohistochemistry with clinical outcomes were assessed in NSCLC patients. DNA methylation of the HGF promoter was correlated with the activation of HGF expression, which induced epithelial-mesenchymal transition, cell migration and invasion. According to the clinical correlation analysis in 63 NSCLC patients, those with high methylation were more likely to have stages III and IV (51.6% vs. 25.0%, P<0.05) and metastasis (57.5% vs. 16.7%, P<0.05) than patients with low methylation. In addition, compared with the protein marker of HGF expression, the DNA methylation marker of the HGF promoter had higher specificity for prognostic analysis of metastases in NSCLC. Our study indicated the regulatory mechanisms related to DNA methylation of the HGF promoter for HGF expression in NSCLC epithelial cells, and suggested that the DNA methylation signature of the HGF promoter could potentially be employed as a biomarker to improve the prognostic accuracy of NSCLC.