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Aspartyl‐asparagyl β hydroxylase over‐expression in human hepatoma is linked to activation of insulin‐like growth factor and notch signaling mechanisms

Aspartyl‐(Asparagyl)‐β‐hydroxylase (AAH) is overexpressed in various malignant neoplasms, including hepatocellular carcinomas (HCCs). The upstream regulation of AAH and its functional role in Notch‐mediated signaling and motility in HCC cells was accessed. The mRNA transcript levels of AAH, insulin receptor substrate (IRS), insulin and insulin‐like growth factor (IGF) receptors and polypeptides, Notch, Jagged, and HES were measured in 15 paired samples of HCC and adjacent HCC‐free human liver biopsy specimens using real‐time quantitative RT‐PCR and Western blot analysis. Overexpression of AAH was detected in 87% of the HCC relative to the paired HCC‐free liver tissue. IRS‐1, IRS‐2, and IRS‐4 were each overexpressed in 80% of the HCC samples, and IGF‐I and IGF‐2 receptors were overexpressed in 40% and 100% of the HCCs, respectively. All HCC samples had relatively increased levels of Notch‐1 and HES‐1 gene expression. Overexpression of AAH led to increased levels of Notch, and co‐immunoprecipitation experiments demonstrated a direct interaction between AAH and Notch as well as its ligand Jagged. In conclusion, contributions to the malignant phenotype of HCC is due to activation of IGF‐I and IGF‐II signaling that results in over‐expression of both AAH and Notch. The functional role of AAH in relation to cell motility has been linked to increased activation of the Notch signaling pathway. (HEPATOLOGY 2006;44:446–457.)