Wu Dan, Yang Xufang, Peng Huiming, Guo Dongmin, Zhao Weiling, Zhao Chen, Zhou Xiaobo
Department of Radiology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
Department of Pathophysiology, MuDanJiang Medical College, Heilongjiang, 150000, P.R.China.
Carcinogenesis. 2017 Sep 1;38(9):910-919. doi: 10.1093/carcin/bgx073.
Hepatocellular carcinoma (HCC) is an aggressive tumor and the third leading cause of cancer-related death worldwide. Ovarian carcinoma immunoreactive antigen-like protein 2 (OCIAD2) has been found frequently methylated in various cancers, including HCC. The aim of the present study was to investigate the role of OCIAD2 in HCC progression. We analyzed liver hepatocellular carcinoma patients' data from the Cancer Genome Atlas (TCGA), including data extracted from 371 HCC tissues and 50 adjacent normal liver tissues. The RNA sequencing and DNA methylation data revealed that OCIAD2 were significantly hypermethylated and its expression level in the tumor tissues was much lower than that in the corresponding adjacent normal tissues. The methylation level in the promoter was negatively correlated with the expression level of OCAID2. Treatment of HCC cell lines with the DNA methylation inhibitor 5-aza-2'-deoxycitydine (5-Aza) induced a significant increase in the OCIAD2 mRNA and protein. Knocking-down OCIAD2 led to an increased colony formation, migration and invasion dramatically, accompanying with an enhanced expression of MMP9 and activation of AKT and FAK. Inhibition of AKT signaling restored OCIAD2-mediated changes in HCC cell clonogenic growth, migration and invasion. Survival analysis of HCC patient's data indicated patients with a higher expression ratio of OCIAD2/MMP9 had a shorter overall survival than those with a lower expression ratio of OCIAD2/MMP9. Overall, our data indicate that reduced expression of OCIAD2 by DNA hypermethylation plays an important role in HCC tumor growth and invasion. Hypermethylation of OCIAD2 may contribute to HCC treatment development.
肝细胞癌（HCC）是一种侵袭性肿瘤，是全球癌症相关死亡的第三大主要原因。卵巢癌免疫反应性抗原样蛋白2（OCIAD2）在包括HCC在内的各种癌症中经常发生甲基化。本研究的目的是探讨OCIAD2在HCC进展中的作用。我们分析了来自癌症基因组图谱（TCGA）的肝细胞癌患者数据，包括从371个HCC组织和50个相邻正常肝组织中提取的数据。RNA测序和DNA甲基化数据显示，OCIAD2显著高甲基化，其在肿瘤组织中的表达水平远低于相应的相邻正常组织。启动子中的甲基化水平与OCAID2的表达水平呈负相关。用DNA甲基化抑制剂5-氮杂-2'-脱氧胞苷（5-Aza）处理HCC细胞系可导致OCIAD2 mRNA和蛋白显著增加。敲低OCIAD2导致集落形成、迁移和侵袭显著增加，同时MMP9表达增强以及AKT和FAK激活。抑制AKT信号通路可恢复OCIAD2介导的HCC细胞克隆生长、迁移和侵袭的变化。对HCC患者数据的生存分析表明，OCIAD2/MMP9表达率较高的患者总生存期短于OCIAD2/MMP9表达率较低的患者。总体而言，我们的数据表明，DNA高甲基化导致的OCIAD2表达降低在HCC肿瘤生长和侵袭中起重要作用。OCIAD2的高甲基化可能有助于HCC治疗的发展。
