Department of Surgery, Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
Ann Surg Oncol. 2012 Jul;19 Suppl 3:S355-64. doi: 10.1245/s10434-011-1797-x. Epub 2011 May 24.
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.
肿瘤内缺氧影响癌症生物学的各个主要方面，但缺氧诱导基因与肝细胞癌之间的关系尚未得到充分研究。从之前与肝细胞癌相关的缺氧诱导基因的微阵列中，我们重点关注一种组蛋白 H3 赖氨酸 9 去甲基酶，称为含有 Jumonji 结构域的 1A（Jumonji domain containing 1A）。该去甲基酶的一个功能是放大缺氧诱导基因的表达。我们假设该去甲基酶将是肝细胞癌的重要标志物。
我们使用实时定量聚合酶链反应和免疫组织化学检查了 110 例肝细胞癌样本中的 Jumonji 结构域 1A 表达。我们进行了小干扰 RNA 抑制分析，以确定该去甲基酶在增殖、侵袭和上皮-间充质转化相关基因表达中的生物学作用。
癌症组织中的 Jumonji 结构域 1A 水平高于正常组织（P < 0.0001）。蛋白表达与基因表达显著相关（P < 0.0001）。Jumonji 结构域 1A 高表达（n = 47）的样本复发率较高（P = 0.0006）。多变量 Cox 回归分析显示，Jumonji 结构域 1A 表达是复发的独立预测因子（P = 0.0016），但与任何临床病理特征均无显著相关性。此外，在缺氧条件下，肝细胞癌细胞系中 Jumonji 结构域 1A 的表达抑制可降低细胞生长抑制、降低侵袭能力，并阻止上皮-间充质转化。
Jumonji 结构域 1A 是一种有用的预后标志物，可改善肝细胞癌的恶性转化。
