Nuclear accumulation of glioma-associated oncogene 2 protein and enhanced expression of forkhead-box transcription factor M1 protein in human hepatocellular carcinoma

The hedgehog (Hh) signaling pathway has been reported to be crucial in human carcinogenesis and tumor progression. Glioma-associated oncogenes (Gli), are zinc finger transcription factors which mediate the transcriptional response to Hh signaling. To explore the role of Gli in the development and progression of hepatocellular carcinoma (HCC), we investigated the expression of Gli2 and FoxM1 (forkhead-box transcription factor M1) which is one of the Gli downstream target genes modulating cell cycle progression in 91 specimens of human HCCs with immunohistochemistry. These immunostaining results were compared with various clinicopathologic parameters. Immunoreactivity of Gli2 and FoxM1 was observed respectively in 84.6% (77/91) and 80.2% (73/91) cases of HCC tumor tissues, and this was considerably higher than expression in the peritumoral tissues. Distribution of Gli2 and FoxM1 proteins in tumor cells was nuclear with or without cytoplasmic staining, or cytoplasmic alone. Statistically, increased nuclear immunopositivity of Gli2 protein correlated significantly with poorer tumor differentiation (P<0.05), as well as with portal vein tumor thrombosis (P<0.05). In addition, overexpression of FoxM1 protein was significantly associated with increased tumor grade (P<0.01) and advanced tumor stage (P<0.05). Moreover, there was a significant association between the expressions of Gli2 and FoxM1 proteins in HCC (r=0.464, P=0.000). This is consistent with the concept that in human HCC, the Hh signaling pathway is involved in the differentiation and proliferation of tumor cells, in part through inducing nuclear accumulation of Gli2 protein and subsequent upregulation of FoxM1 protein.