Abstract Number:

3046
Presentation Title:

Sonic Hedgehog (SHH)-Gli pathway is responsible for the growth and dedifferentiation of hepatocelluar carcinoma (HCC) cells
Presentation Start/End Time:

Monday, Apr 03, 2006, 1:00 PM - 5:00 PM
Location:

Exhibit Hall, Washington Convention Center
Poster Section:

15
Poster Board Number:

12
Author Block:

Youngsoo Kim, Nicholas M. Dean, Eric G. Marcusson. ISIS Pharmaceuticlas Inc., Carlsbad, CA
In order to identify drug targets for antisense oligonucleotides (ASOs) therapeutics for the treatment of hepatocelluar carcinoma (HCC), microarray analysis was performed on a SV40 driven mouse model of HCC. After this process, approximately 40 targets were selected for further investigation in HCC cell lines by simple high-throughput assays. From this initial round of screening, we identified SHH-Gli pathway as an important pathway for therapeutic intervention of HCC. The SHH-Gli pathway plays key roles during normal embryo development. When it is aberrantly activated, however it contributes to the development of various types of cancer. Constitutive activation of this pathway often occurs in normal tissues when they are under chronic injury and inflammation, which are known causes of HCC development. HCCs become poorly differentiated as they advance to more malignant forms. In an attempt to understand how the SHH-Gli pathway is involved in the development of HCC, we first investigated the degree of differentiation of human HCC cell lines by comparing the expression levels of various differentiation markers. Next, we investigated whether the components of the SHH-Gli pathway are expressed and whether the pathway is functionally active in HCC lines. Finally, we examined how specific downregulation of each component in the pathway would affect gene expression and phenotypes in HCC lines with different degrees of differentiation. We found that the SHH-Gli pathway is functionally active in various HCC lines using a reporter gene assay. Although the expression levels of SHH-Gli pathway components varied, Gli2 levels were much higher in poorly differentiated HCC. In addition, Gli2 expression increased as liver tissue became cancerous in a SV40 transgenic mouse model of HCC. Furthermore, selective downregulation of Gli2 by ASOs led to the inhibition of cell proliferation and promotion of apoptosis in various HCC cell lines in a manner that was independent of its expression level, while ablation of other components of the pathway had little effect on cell viability. Taken together, these results suggest that SHH-Gli pathway is important for the development of HCC and a selective inhibition of Gli2 may provide a useful tool for the treatment of HCC.