HIGH EXPRESSION OF TRUNCATED GLI3 IS ASSOCIATED WITH POOR OVERALL SURVIVAL IN PATIENTS WITH NON-SMALL-CELL LUNG CANCER

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Abstract

Background

The hedgehog (Hh) pathway is involved in embryogenesis and organogenesis. Recent studies have shown that aberrant activation of the Hh pathway is closely correlated with various types of human malignancies. GLI3 is one of the zinc-finger transcription factors in the Hh signaling pathway, which exist in both full-length activator (GLI3FL) and truncated repressor (GLI3TR) forms. We investigated GLI3 expression in patients with non-small-cell lung cancer (NSCLC). The role of GLI3 in lung carcinogenesis and its correlation with clinicopathological factors and overall survival (OS) in patients with NSCLC were explored.

Methods

GLI3FL and GLI3TR expression were analyzed immunohistochemically in 330 and 352 evaluable NSCLC tissues, respectively. The association between GLI3FL and GLI3TR expression and clinicopathological parameters and OS were statistically analyzed.

Results

GLI3FL immunohistochemical staining could be observed in the cytoplasm of malignant epithelial (GLI3FLepithelial) and stromal cells (GLI3FLstroma). GLI3TR staining could be observed in nucleus of malignant epithelial cells. High-level expression of GLI3FLepithelial, GLI3FLstroma and GLI3TR were 52.7%, 85.3% and 45.2% respectively. GLI3FLepithelial and GLI3FLstroma were not significantly correlated with any clinicopathological parameter and survival. However, high expression of GLI3TR was significantly associated with lymph node metastasis (P = 0.013) and poor OS (28.4 versus 40.8 months, P = 0.010). In patients with adenocarcinoma of high and low GLI3TR expression, the median OS were 27.7 and 50.6 months, respectively (P = 0.004). Importantly, multivariate analysis showed that GLI3TR expression, tumor differentiation, disease stage (P = 0.001) were independent prognostic factors for patients with NSCLC.

Conclusions

Hh pathway is activated in NSCLC. Overexpression of GLI3TR in NSCLC, especially in adenocarcinoma, is associated with poor prognosis. GLI3TR expression is an independent prognostic factor in OS. GLI3FL and GLI3TR may play different roles in the tumorigenesis of NSCLC.

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