Gli-2 expression was associated with poor prognosis of hepatocellular carcinoma

Abstract

Background and Aims: The Sonic hedgehog (SHH) pathway acts as a regulator of development, homeostasis, and reparative processes in endodermal tissues, including the gastrointestinal tracts. Abnormal expression or mutation of SHH components has been reported in esophageal, gastric, duodenal, and pancreatic cancers. SHH-pathway-targeted therapies have been developed and applied in the management of upper-GI tract cancer. We aimed to study the expression status of several molecules in the SHH signal pathway in hepatocellular carcinoma (HCC) and the clinicopathologic features of HCCs according to their expression status. Methods: We assessed the expression status of the SHH ligand, Patched (PTCH), and oncogenes (Gli-1, Gli-2 and Gli-3) by immunohistochemistry in 407 HCCs blocked in 13 tissue microarrays and evaluated the clinicopathologic features, including CK19-positive biliary phenotype. Results: The positive rates for SHH, PTCH, Gli-1, Gli-2 and Gli-3 were 49.1%, 10.1%, 1.5%, 17.0%, and 1.5%, respectively. Comparative analysis with clinicopathologic parameters revealed that the positive expression rate for SHH was higher in males than in females and was higher in patients whose preoperative alpha-fetoprotein level was higher than normal (all p < 0.05). Gli-2 expression was prominent in females and in patients whose tumor had a high Edmondson-Steiner nuclear grade , dedifferentiated histology (e.g., solid or spindle cell morphology), high pT stage, and CK19 positivity (all p < 0.05). The expression levels of PTCH, Gli-1 and Gli-3 were not associated with a significant difference in tumor features. Only positive Gli-2 expression was associated with a shorter disease-free survival (DFS) and overall survival (OS) time (10 vs 34 months, 53 vs 181 months, all p < 0.05). Gli-2 expression was an independent prognostic factor according to multivariate Cox analysis, including nuclear grade, vascular invasion, multiplicity, size and extent of invasion (p = 0.015). Conclusion: The results suggest that Gli-2 could be an independent prognostic factor and a therapeuric target for HCC.