Aspartyl-(asparaginyl)-beta-hydroxylase regulates hepatocellular carcinoma invasiveness.

Abstract

BACKGROUND/AIMS:

We measured aspartyl (asparaginyl)-beta-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-DeltaC) 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-DeltaC 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.

• Authors: Suzanne M de la Monte, Seishu Tamaki, M Chiara Cantarini, Nedim Ince, Marcus Wiedmann, Jade J Carter, Stephanie A Lahousse, Sophia Califano, Takashi Maeda, Takato Ueno, Antonia D'Errico, Franco Trevisani, Jack R Wands
• Journal: Journal of hepatology (J Hepatol) Vol. 44 Issue 5 Pg. 971-83 (May 2006) ISSN: 0168-8278 [Print] Netherlands
• PMID: 16564107 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Hypoglycemic Agents
• IRS1 protein, human
• Insulin
• Insulin Receptor Substrate Proteins
• Irs1 protein, mouse
• Phosphoproteins
• Epidermal Growth Factor
• Insulin-Like Growth Factor I
• Mixed Function Oxygenases
• aspartic acid 2-oxoglutarate-dependent dioxygenase

Topics

• Animals
• Biopsy
• Carcinoma, Hepatocellular (metabolism, secondary)
• Cell Line, Tumor
• Cell Movement (drug effects, physiology)
• Epidermal Growth Factor (pharmacology)
• Gene Expression Regulation, Enzymologic
• Gene Expression Regulation, Neoplastic
• Humans
• Hypoglycemic Agents (pharmacology)
• Insulin (pharmacology)
• Insulin Receptor Substrate Proteins
• Insulin-Like Growth Factor I (pharmacology)
• Liver Neoplasms (metabolism, pathology)
• Mice
• Mice, Transgenic
• Mixed Function Oxygenases (genetics, metabolism)
• Neoplasm Invasiveness
• Phosphoproteins (metabolism)
• Signal Transduction (drug effects, physiology)