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.
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