Role of the Hypoxia-Related Gene, JMJD1A, in Hepatocellular Carcinoma: Clinical Impact on Recurrence after Hepatic Resection

Abstract

Intratumoral hypoxia affects every major aspect of cancer biology, but the relationship between hypoxia-induced genes and hepatocellular carcinoma has not been fully investigated. From a previously ranked microarray of hypoxia-inducible genes related to hepatocellular carcinoma, we focused on a histone H3 lysine 9 demethylase, known as Jumonji domain containing 1A. One function of this demethylase is to amplify hypoxia-inducible gene expression. We hypothesized that the demethylase would be a significant marker of hepatocellular carcinoma. We examined Jumonji domain containing 1A expression in 110 hepatocellular carcinoma samples with quantitative real-time polymerase chain reaction and immunohistochemistry. We performed a small interfering RNA suppression analysis to determine the biological roles of the demethylase in proliferation, invasion, and the expression of epithelial-mesenchymal transition-related genes. The level of Jumonji domain containing 1A in cancer tissues was higher than in normal tissues (P < 0.0001). Protein expression was significantly related to gene expression (P < 0.0001). Samples with high Jumonji domain containing 1A expression (n = 47) had higher recurrence rates (P = 0.0006) than those with low expression. Multivariate Cox regression analysis revealed that Jumonji domain containing 1A expression was an independent predictor of recurrence (P = 0.0016), but was not significantly associated with any clinicopathological characteristics. Moreover, suppression of Jumonji domain containing 1A expression in hepatocellular carcinoma cell lines under hypoxic conditions reduced cell growth inhibition, reduced invasion ability, and arrested epithelial-mesenchymal transitions. Jumonji domain containing 1A is a useful prognostic marker and may ameliorate malignant transformation in hepatocellular carcinoma.