Back to Search
Start Over
Aspartyl-(asparaginyl)-β-hydroxylase regulates hepatocellular carcinoma invasiveness
- Source :
-
Journal of Hepatology . May2006, Vol. 44 Issue 5, p971-983. 13p. - Publication Year :
- 2006
-
Abstract
- Background/Aims: We measured aspartyl (asparaginyl)-β-hydroxylase (AAH) gene expression in human hepatocelluar carcinoma and surrounding uninvolved liver at both the mRNA and protein level and examined the regulation and function of this enzyme. Methods: Since growth of HCC is mediated by signaling through the insulin-receptor substrate, type 1 (IRS-1), we examined—if AAH is a downstream gene regulated by insulin and IGF-1 in HCC cells. In addition, IRS-1 regulation of AAH was examined in a transgenic (Tg) mouse model in which the human (h) IRS-1 gene was over-expressed in the liver, and an in vitro model in which a C-terminus truncated dominant-negative hIRS-1 cDNA (hIRS-ΔC) was over-expressed in FOCUS HCC cells. The direct effects of AAH on motility and invasiveness were examined in AAH-transfected HepG2 cells. Results: Insulin and IGF-1 stimulation increased AAH mRNA and protein expression and motility in FOCUS and Hep-G2 cells. These effects were mediated by signaling through the Erk MAPK and PI3 kinase-Akt pathways. Over-expression of hIRS-1 resulted in high levels of AAH in Tg mouse livers, while over-expression of hIRS-ΔC reduced AAH expression, motility, and invasiveness in FOCUS cells. Finally, over-expression of AAH significantly increased motility and invasiveness in HepG2 cells, whereas siRNA inhibition of AAH expression significantly reduced directional motility in FOCUS cells. Conclusions: The results suggest that enhanced AAH gene activity is a common feature of human HCC and growth factor signaling through IRS-1 regulates AAH expression and increases motility and invasion of HCC cells. Therefore, AAH may represent an important target for regulating tumor growth in vivo. [Copyright &y& Elsevier]
- Subjects :
- *LIVER cancer
*GENE expression
*GENETIC regulation
*CHOLESTEROL hydroxylase
Subjects
Details
- Language :
- English
- ISSN :
- 01688278
- Volume :
- 44
- Issue :
- 5
- Database :
- Academic Search Index
- Journal :
- Journal of Hepatology
- Publication Type :
- Academic Journal
- Accession number :
- 20398753
- Full Text :
- https://doi.org/10.1016/j.jhep.2006.01.038