Journal of Clinical & Experimental Pathology
Open Access

Abstract

Background & Aims: Ten eleven translocation (TET) enzymes convert 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC) and play crucial roles in biological and pathological processes by mediating DNA demethylation; however, the functional role of this epigenetic mark and the related enzymes in hepatocellular carcinoma (HCC) progression remains unknown. Methods: We analyzed 5-hmC levels using tissue microarray from a 323 HCC patient cohort. We determined RNA expression levels of TET family proteins, the TET expression-silencing microRNA-29a, and suppressor of cytokine signaling 1 (SOCS1) in 108 HCC patients. The methylation status of SOCS1 promoter was examined using glucosylation of genomic 5-hmC followed by methylation sensitive polymerase chain reaction (glucMS-qPCR). We determined miR-29a and TET family membersā?? functional effects using RNA interference and transgenic expression in HCC cells and evaluated xenograft tumor growth in nude mice. Results: TET family enzymes down regulation is one likely mechanism underlying 5-hmC loss in HCC. There was a significant inverse correlation between miR-29a and TET expression in HCC tissues. Dot blot assay revealed that miR-29a up regulation and down regulation in HCC cells yields distinct global DNA hydroxymethylation patterns, and that increased DNA methylation of SOCS1 promoter is associated with miR-29a overexpression in HCC cells. Furthermore, miR-29a silencing anti-metastatic SOCS1 through direct TET family targeting, resulting in SOCS1 promoter demethylation inhibition. Finally, miR-29a overexpression correlates with poor clinical outcomes and TET-Family-SOCS1-matrix metalloproteinase (MMP) 9 axis silencing in HCC patients. Conclusions: These findings demonstrate that 5-hmC loss is an epigenetic hallmark of HCC, and miR-29a is an important epigenetic modifier, promoting HCC metastasis through TET family targeting. Moreover, these results offer a new strategy for epigenetic cancer therapy.

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