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.