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.
Highlights
As an important determinant in normal embryonic development, the hedgehog pathway plays crucial roles in tissue patterning, cell differentiation, and cell proliferation [1]
To determine the relative expression of sonic hedgehog (Shh)-glioma-associated oncogenes (Gli) pathway components in hepatocellular carcinoma (HCC) cell lines compared with normal liver, reverse transcription-PCR (RT-PCR) was done www.aacrjournals.org
All of the components of the pathway were expressed in HCC lines to different extents, Ptch1, Gli1, and Gli2 levels were much higher in many HCC lines relative to normal liver
Summary
As an important determinant in normal embryonic development, the hedgehog pathway plays crucial roles in tissue patterning, cell differentiation, and cell proliferation [1]. The pathway remains inactive in most normal mature tissues, except during tissue repair, it can contribute to the development of various pathophysiologic conditions, including cancer, when aberrantly activated [2, 3]. Doi:10.1158/0008-5472.CAN-06-3040 www.aacrjournals.org has indicated constitutive activation of the signaling pathway in cancers with gastrointestinal origins, such as in prostate [4,5,6], pancreatic [7], gastric [8], and colon [9, 10]. Other mechanisms, including overexpression of sonic hedgehog (Shh) and Glis, loss of function of suppressors, such as Ptch and SuFu, and gain of function of the activator Smo, are responsible for the activation of this pathway in cancer [7, 11, 12]
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