Expression of the GLI family genes is associated with tumor progression in advanced lung adenocarcinoma

BACKGROUND The hedgehog (Hh) signaling pathway is aberrantly activated in various cancers. Expression of the GLI family of genes, which encode for transcriptional factors of the Hh pathway, has not been fully assessed in clinical samples of advanced lung adenocarcinoma. In this study, we retrospectively evaluated the expression of the GLI family of genes in advanced stage lung adenocarcinoma samples and determined their relation to patient survival. METHODS The levels of GLI1, GLI2, and GLI3 mRNA expression were measured by quantitative real-time polymerase chain reaction in surgically obtained tissue samples from stage II-IV lung adenocarcinoma patients (n = 102). Pairwise comparisons between all three GLI mRNA expression were performed, and after dichotomizing the patients into low and high expression groups according to each GLI mRNA expression level, survival curves were calculated and multivariate analyses were conducted. RESULTS Significant positive correlation was found between GLI1 and GLI3 mRNA expression (P <0.001). Tumors with higher expression (upper 15%) of GLI1 or GLI3 mRNA were associated with poor survival in stage II-IV (5-year overall survival rates: GLI1 mRNA low, 41.7% vs. high, 20.0%, P = 0.0074; GLI3 mRNA low, 43.1% vs. high, 13.3%, P = 0.0062) and stage III-IV (5-year overall survival rates: GLI1 mRNA low, 34.0% vs. high, 0%, P = 0.0012; GLI3 mRNA low, 33.4% vs. high, 7.7%, P = 0.057) lung adenocarcinoma patients. GLI2 mRNA expression did not appear to have great clinical significance. Multivariate analysis revealed higher GLI1 mRNA expression as an independent factor for unfavorable patient survival (P = 0.0030, hazard ratio = 3.1, 95% confidence interval = 1.5-6.2), as well as tumor differentiation and stage. CONCLUSIONS Expression of GLI1 and GLI3 mRNA was strongly correlated, and their overexpression, especially that of GLI1, was found to be predictive of aggressive tumor behavior. This study indicates that the Hh pathway may be a key oncogenic signaling network in tumor pathogenesis and, thus, a potential therapeutic target in advanced lung adenocarcinoma.