In recent years, long noncoding RNAs (lncRNAs) have been shown to have critical regulatory roles in cancer biology. However, the contributions of lncRNAs to hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) remain largely unknown. Differentially expressed lncRNAs between HBV-related HCC and paired peritumoral tissues were identified by microarray and validated using quantitative real-time polymerase chain reaction. Liver samples from patients with HBV-related HCC were analyzed for levels of a specific differentially expressed lncRNA High Expression In HCC (termed lncRNA-HEIH); data were compared with survival data using the Kaplan-Meier method and compared between groups by the log-rank test. The effects of lncRNA-HEIH were assessed by silencing and overexpressing the lncRNA in vitro and in vivo. The expression level of lncRNA-HEIH in HBV-related HCC is significantly associated with recurrence and is an independent prognostic factor for survival. We also found that lncRNA-HEIH plays a key role in G 0 /G 1 arrest, and further demonstrated that lncRNA-HEIH was associated with enhancer of zeste homolog 2 (EZH2) and that this association was required for the repression of EZH2 target genes. Conclusions: Together, these results indicate that lncRNA-HEIH is an oncogenic lncRNA that promotes tumor progression and leads us to propose that lncRNAs may serve as key regulatory hubs in HCC progression. (HEPATOLOGY 2011;54:1679-1689 H epatocellular carcinoma (HCC) is one of the most common human cancers worldwide, particularly in Southeast Asia and Africa. 1More than 70%-80% of HCC cases occur in high hepatitis B virus (HBV) endemic regions, and 50% of HCC cases worldwide are attributable to chronic infection with HBV. Unfortunately, the 5-year survival rate of HBV-related HCC patients remains poor, and approximately 600,000 HCC patients die each year, despite recent advances in surgical techniques and medical treatment.2 Although previous studies identified many aberrantly expressed protein-coding genes in HCC, novel molecular markers that can help in early diagnosis and risk assessment are still urgently needed. 3It is of paramount importance to understand the relationships between clinical symptoms and molecular changes in HCC for developing new diagnosis and treatment strategies for HCC and improving the prognosis of diagnosed patients. The human transcriptome comprises not only large numbers of protein-coding messenger RNAs (mRNAs), but also a large set of nonprotein coding Abbreviations:: CCK-8, Cell-Counting Kit-8 assay; ChIP, chromatin immunoprecipitation; cDNA, complementary DNA; 95% CI, 95% confidence interval; EZH2, enhancer of zeste homolog

BackgroundSeveral of the thousands of human long noncoding RNAs (lncRNAs) have been functionally characterized, yet their potential involvement in hepatocellular carcinoma (HCC) remains poorly understood.MethodsLncRNA-HOXD-AS1 was identified by microarray and validated by real-time PCR. The clinicopathological significance of HOXD-AS1 was analyzed by Kaplan-Meier method. Chromatin immunoprecipitation was conducted to examine the mechanism of HOXD-AS1 upregulation. The role of HOXD-AS1 in HCC cells was assessed both in vitro and in vivo. ceRNA function of HOXD-AS1 was evaluated by RNA immunoprecipitation and biotin-coupled miRNA pull down assays.ResultsIn this study, we found that HOXD-AS1 was significantly upregulated in HCC tissues. Clinical investigation demonstrated high expression level of HOXD-AS1 was associated with poor prognosis and high tumor node metastasis stage of HCC patients, and was an independent risk factor for survival. Moreover, our results revealed that STAT3 could specifically interact with the promoter of HOXD-AS1 and activate HOXD-AS1 transcription. Knockdown of HOXD-AS1 significantly inhibited migration and invasion of HCC cells in vitro and distant lung metastasis in vivo. Additionally, HOXD-AS1 was enriched in the cytoplasm, and shared miRNA response elements with SOX4. Overexpression of HOXD-AS1 competitively bound to miR-130a-3p that prevented SOX4 from miRNA-mediated degradation, thus activated the expression of EZH2 and MMP2 and facilitated HCC metastasis.ConclusionsIn summary, HOXD-AS1 is a prognostic marker for HCC patients and it may play a pro-metastatic role in hepatocarcinogenesis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-017-0680-1) contains supplementary material, which is available to authorized users.