Selective Down-Regulation of Glioma-Associated Oncogene 2 Inhibits the Proliferation of Hepatocellular Carcinoma Cells

Abstract

The sonic hedgehog (Shh) pathway contributes to the initiation and progression of tumors with various origins when aberrantly activated. In this study, we investigated if the Shh pathway is important for the proliferation of hepatocellular carcinoma (HCC) cells and also began to identify which components of the pathway play a pivotal role in the biology of HCC. Expression levels of components in the pathway were measured, and glioma-associated oncogene (Gli) 2 levels were found to be considerably higher in human HCC lines compared with normal liver. Gli2 levels were also higher in tumor tissue from HCC patients compared with normal liver. Antisense oligonucleotides (ASO) were used to specifically down-regulate Gli2, and this led to decreased proliferation of various HCC cell lines. However, inhibition of Gli1 and Gli3 with ASOs did not decrease proliferation in most HCC cell lines and inhibitors targeting the upstream components of the pathway, including smoothened (Smo), displayed antiproliferative effects in only a subset of HCC cell lines. Moreover, in cancer cells harboring Smo mutations or unresponsive to the Smo inhibitor 3-keto-N-aminoethylaminoethylcaproyldihydrocinnamoyl cyclopamine, the Gli2 ASO was still able to inhibit proliferation. The importance of Gli2 in HCC proliferation was further confirmed by the changes in expression levels of genes, such as Bcl-2, c-Myc, and p27, following suppression of Gli2 expression. Taken together, these results suggest that, among the Gli transcription factors, Gli2 plays a predominant role in the proliferation of HCC cells and the suppression of Gli2 expression may provide a useful therapeutic option for the treatment of HCC. [Cancer Res 2007;67(8):3583-93]

Hedgehog signaling pathway mediates invasion and metastasis of hepatocellular carcinoma via ERK pathway

“…Previous evidence has demonstrated that the Hh signaling plays an important role in multiple tumor types. This signaling pathway is involved in and participates development, invasion and metastasis of HCC [34][35][36][37][38][39][40] . In this study, we further detected expression of Shh and Gli1 in metastasis and non-metastasis HCC liver tissues, simultaneously we used KAAD-cyc, a specific inhibitor of Hh pathway and Shh, a ligand of the Hh pathway in invasion and metastasis assays of human HCC cell line, and we confirmed the results.…”

“…Recent studies have revealed that the Hh signaling pathway is abnormally activated in human HCC [34][35][36] , and this pathway is thought to participate in the development of HCC [37][38][39] . Moreover, activation of the Hh pathway is correlated closely to invasion and metastasis of HCC [36,40] .…”

Differential expression profiles of the Hedgehog signaling pathway between microsatellite-stable and microsatellite-unstable colorectal cancers

“…Thus, the Hh signaling pathway may play a crucial role in tumorigenesis when reactivated in adult tissues (4)(5)(6)(7)(8). The involvement of the Hh signaling pathway in CRC has demonstrated that it is essential for human CRC growth, recurrence, metastases and stem cell expansion (9).…”

Interaction of major genes predisposing to hepatocellular carcinoma with genes encoding signal transduction pathways influences tumor phenotype and prognosis

“…This results in GLI proteins activation and nuclear translocation, where they activate target gene transcription [109] . According to recent observations GLI2 is overexpressed in some HCC cell lines, and its inhibition by antisense oligonucleotides inhibits cell proliferation [110] . GLI1 overexpression occurs in a lower number of HCC cell lines and its inhibition causes lower decrease in growth rate [110] .…”

“…According to recent observations GLI2 is overexpressed in some HCC cell lines, and its inhibition by antisense oligonucleotides inhibits cell proliferation [110] . GLI1 overexpression occurs in a lower number of HCC cell lines and its inhibition causes lower decrease in growth rate [110] . High levels of phosphorylated ERK1/2 (pERK1/2) and Gli1 proteins occur in neoplastic nodules and HCC induced by the resistant hepatocyte protocol in F344 rats and, at a lower extent, in BN rats (Feo et al, unpublished results).…”