GLI1 is induced only upon activation of the HH pathway (24,26). Therefore, as a transcription factor, GLI1 expression is a good indicator of HH pathway activation. sellekchem Recent studies showed that Gli1 controls several biological characteristics, such as proliferation and invasion, in several types of cancers (17,19,26). Although the activation of the HH pathway is involved in several types of gastrointestinal cancers and other cancers, its role in HCC pathogenesis is not well understood. The normal hepatocytes lack the HH signaling pathway (1,23). However, the activation of the HH pathway in endodermal progenitors is essential for liver development. Thus, we hypothesized that regulation of the HH signaling may be involved in hepatocarcinogenesis. Our data indicated that HH signaling is frequently activated in HCC.

SHH and its target genes, PTCH1, SMOH and GLI1, were frequently expressed in the tumor tissues than in the adjacent liver tissues. These data support our hypothesis that activation of the HH pathway is essential in the development of HCC. Since the HH signaling pathway is frequently activated in HCC, the markers for the activation, including SHH, SMOH, PTCH1 and GLI1, may be useful for diagnosis of liver cancers. Sicklick (1) reported that the expression of SMOH proto-oncogene is positively correlated with HCC tumor size. Our results also showed that overexpression of SMOH mRNA in HCC was positively correlated with HCC tumor size. Thus, it can be a prognostic indicator in HCC biology. Although the serum AFP level was inversely correlated with DFS and OS, it was not related to the expression of SHH pathway genes.

Moreover, the tumor size was also inversely correlated with DFS and OS, but with no statistically significant relationship. This data showed that SMOH activation is a potential prognostic indicator of human HCC. Ten Haaf, et al. (24) found that the increased expression of GLI1 protein in breast cancer is significantly correlated with unfavorable OS. Souzaki, et al. (26) reported that the %GLI1 nuclear translocation in lymph nodes with micro-metastasis was higher than that in ductal carcinoma in situ (DCIS) with microinvasion and DCIS. The progression from DCIS to invasive ductal carcinoma (IDC) requires a certain level of %GLI1 nuclear translocation and the HH pathway contributes to the progression from DCIS. He, et al.

(28) also reported that patients with positive expression of SHH, PTCH1 and GLI1 proteins showed poorer DFS and OS than those with negative expression, and these proteins were independent, unfavorable prognostic factors. In this study, we found that GLI1 expression in HCC tissues showed a significant Drug_discovery relationship with DFS and OS. The simultaneous positive expression of GLI1 gene in tumor and adjacent non-tumor liver tissues was significantly related with clinical prognosis.