Background & Aims: Although numerous long non-coding RNAs (lncRNAs) have been identified in mammals, many of their biological roles remain to be characterized.Recently, long non-coding RNAs (LncRNAs) encoded in human genome have been shown to serve as important regulatory transcripts and may have other previously unappreciated functions.They can serve as scaffolds, aiding the association of proteins with genomic DNA.In our recent study, we identified nonoverlapping signatures of a small number of lncRNAs that are aberrantly expressed in human Hepatitis B virus (HBV)-related HCC compared with matched periturnoral tissues.Among these lncRNAs, H19 was found to play a potential role in HCC progression.Early reports suggest that H19 contributes to carcinogenesis, including hepatocellular carcinoma (HCC).Examination of the Oncomine resource showed that most HCC cases express H19 at a level that is comparable with the liver, with a tendency toward lower expression.This is consistent with our previous microarray data and indicates a more complicated role of H19 in HCC that needs to be characterized.Methods & Results: In this study, the expression level of H19 was assessed in different regions of HCC patientsliver samples.Notably, our results showed that the H19 RNA was enriched in the sections around the tumor tissues.This is in agreement with a previousreport that H19 was most prominent at the boundary of the tumor nodule.We collected tissues from different sites of the patientslivers, and we defined the peritumoral tissues as the sections that were 2 cm away from the tumor tissues and the normal tissues as the sections that were at least 3 cm away from the tumors.Loss-and gain-of-function studies on this lncRNA in the HCC cell lines, SMMC7721 and HCCLM3, were used to characterize its effects on gene expression and to assess its effect on HCC metastasis both in vitro and in vivo.In this study, we show that H19 was underexpressed in intratumoral HCC tissues (T), as compared with peritumoral tissues (L).Additionally, low T/L ratio of H19 predicted poor prognosis.The extremely poor prognosis of patients with HCC is largely due to the high frequency of tumor recurrence or metastasis after surgical resection.Epithelial-to-mesenchymal (EMT) and mesenchymal-to-epithelial transitions play crucial roles in the progress of cancer metastasis.In particular, EMT has been found to contribute to the metastatic dissemination of the tumor and the acquisition of therapeutic resistance.Conclusions: In this study, we found that H19 suppressed HCC progression metastasis and the expression of markers of epithelial-to-mesenchymal transition.Furthermore, H19 associatedwith the protein complex hnRNP U/PCAF/RNAPol Ⅱ, activating miR-200 family by increasing histone acetylation.The results demonstrate that H19 can alter the miR-200 pathway, thus contributing to mesenchymal-to-epithelial transition and to the suppression of tumor metastasis.These data provide an explanation for the hitherto puzzling literature on the relationship between H19 and cancer, and could suggest the development of combination therapies that target H19 and the miR-200 family.Taken together, this study clearly demonstrates a crucial role of H19 in HCC individual therapy and better curative effects and the prognostic significance of H1 9 and miR-200 family expression in HCC progeression.