Overexpression of Aspartyl-(Asparaginyl)-β-Hydroxylase in Hepatocellular Carcinoma Is Associated With Worse Surgical Outcome

Abstract

The association between the overexpression of aspartyl-(asparaginyl)-b-hydroxylase (AAH) and the invasiveness of hepatocellular carcinoma (HCC) in vitro has been reported. However, the prognostic value of AAH expression in HCC remains unclear. The purpose of this study was to investigate the relationship between AAH expression, tumor recurrence, and patient survival. We identified AAH as the most overexpressed gene in HCC by way of complementary DNA microarray hybridization. A prospective study of 233 patients undergoing curative resection indicated that AAH expression was an independent factor affecting recurrence (hazard ratio [HR] 3.161, 95% confidence interval [CI] 2.115-4.724, P < 0.001) and survival (HR 2.712, 95% CI 1.734-4.241, P < 0.001). Patients with AAH overexpression had a poorer prognosis than those with AAH underexpression (P < 0.001 for both recurrence and survival). In Barcelona Clinic Liver Cancer stage A patients with AAH overexpression or underexpression, the tumor recurrence and survival rates were also statistically different (45% and 85% versus16% and 33% in 1-and 3-year cumulative recurrence rates, respectively; 73% and 37% versus 90% and 80% in 1-and 3-year survival rates, respectively; P < 0.001 for both). Furthermore, in stage A patients with tumors measuring 5 cm in diameter, the time to recurrence was 26.7 6 1.6 versus 51.9 6 2.8 months, and the 1-and 3-year survival rates were 97% and 52% versus 100% and 90% in AAH overexpression and underexpression patients, respectively (P < 0.001 for both). Conclusion: AAH overexpression in HCC is strongly correlated with worse surgical outcome, and this molecule likely provides a more precise prognostic predictor in early stage HCCs. (HEPATOLOGY 2010;52:164-173) H epatocellular carcinoma (HCC) is one of the most prevalent malignant neoplasms worldwide 1 and is the second leading cause of cancer-related deaths in China.2 Both hepatic resection and liver transplantation are considered as potential curative treatments for well-selected HCC patients. As far as curative resection is concerned, surgical prognosis for many patients with HCC is not favorable due to the likelihood of intrahepatic and extrahepatic recurrence, which leads to a high mortality rate.3-5 Several prognostic staging systems have been established in clinical practice allowing clinicians to predict HCC outcome.6-8 Nevertheless, correlations are not always found between tumor stage and the actual prognosis, and this phenomenon is more common in patients with early HCC than in those with advanced HCC. Considering that HCC is increasingly diagnosed and resected at an early stage and that current staging systems have some limitations in the prognostic evaluation of early HCC, 4,9,10 efforts have been made to

Downregulation of nuclear receptor FXR is associated with multiple malignant clinicopathological characteristics in human hepatocellular carcinoma

“…Primary antibodies against FXR (R&D Systems, Minneapolis, MN, 1:100), SHP (MBL, Woburn, MA, 1:200), and Ki67 (Maixin Bio, Fuzhou, China, 1:50) were used to detect the corresponding proteins. The results of immunohistochemical staining were analyzed as previously described (19). The proliferative index was calculated as the percentage of Ki67-positive cells.…”

Potential Role of Phosphorylation as a Regulator of Aspartyl-(asparaginyl)-β-hydroxylase: Relevance to Infiltrative Spread of Human Hepatocellular Carcinoma

“…AAH can be regarded as a distinct biomarker of hepatocellular carcinoma and a prognosticator of aggressiveness or responsiveness to treatment [11,12,17]. Insulin and IGF-1 stimulate AAH expression and function, resulting in increased cell adhesion and motility [11,12,13,31,32,38,39].…”

“…Importantly, insulin/IGF signaling regulates expression and function of aspartyl-(asparaginyl)-β-hydroxylase (AAH), which promotes cell motility and invasion [11,12,13,14]. Moreover, AAH could serve as a biomarker for HCC because its expression correlates with malignant transformation, aggressive histological grade, response to treatment, and prognosis [11,15,16,17]. …”

Early intrahepatic recurrence of hepatocellular carcinoma after hepatectomy treated with re-hepatectomy, ablation or chemoembolization: A prospective cohort study

“…18 After re-hepatectomy, the patients were followed-up once every 2 months within the first 2 years, and then once every 3 months thereafter. Patients who received PRFA and TACE for HCC recurrence underwent a similar follow-up regimen as those who received re-hepatectomy.…”