Aspartyl-asparagyl β hydroxylase over-expression in human hepatoma is linked to activation of insulin-like growth factor and notch signaling mechanisms
✍ Scribed by M. Chiara Cantarini; Suzanne M. de la Monte; Maoyin Pang; Ming Tong; Antonia D'Errico; Franco Trevisani; Jack R. Wands
- Book ID
- 102849450
- Publisher
- John Wiley and Sons
- Year
- 2006
- Tongue
- English
- Weight
- 828 KB
- Volume
- 44
- Category
- Article
- ISSN
- 0270-9139
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✦ Synopsis
Aspartyl-(Asparagyl)--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.)
H epatocellular carcinoma (HCC) is a common malignant neoplasm worldwide, with prevalence rates that parallel the distributions of hepatitis virus infections. The highest incidences of HCC are in sub-Saharan Africa and southeastern Asia, where hepatitis B virus infection is endemic and HCC is a leading cause of cancer death. 1 Within the last two decades, the incidence of HCC has increased in many developed countries due to spreading of hepatitis C virus infection. 2,3 HCC usually arises in the setting of chronic liver disease, including cirrhosis, which is present in up to 80% of cases of HCC. Therefore, cirrhosis may itself be considered a major risk factor for HCC. Although chronic hepatitis B virus and hepatitis C virus infections carry the highest risk for developing HCC, 4 co-factors leading to chronic liver disease and contributing to the pathogenesis of HCC include chronic alcohol abuse, metabolic diseases such as non-alcoholic steatosis, and hemochromatosis. 4 In addition, exposure to environmental toxins that cause DNA damage, such as aflatoxin, is an established risk factor for HCC. 5,6 An immunological approach used to identify novel proteins that distinguish HCC from non-transformed liver tissue led to the identification and isolation of human aspartyl-asparaginyl -hydroxylase (AAH). 7,8 AAH is a type 2 transmembrane protein that has a predicted molecular mass of approximately 86 kd. AAH is a member of the ␣-ketoglutaratedependent dioxygenase family of molecules and catalyzes the hydroxylation of specific aspartyl and asparaginyl residues in epidermal growth fac-