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Long noncoding RNA GIHCG promotes hepatocellular carcinoma progression through epigenetically regulating miR-200b/a/429

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Abstract

Long noncoding RNAs (lncRNAs) have been reported to play pivotal roles in a variety of cancers. However, lncRNAs involved in hepatocellular carcinoma (HCC) initiation and progression remain largely unclear. In this study, we identified an lncRNA gradually increased during hepatocarcinogenesis (lncRNA-GIHCG) using publicly available microarray data. Our results further revealed that GIHCG is upregulated in HCC tissues in comparison with adjacent non-tumor tissues. High GIHCG expression is correlated with large tumor size, microvascular invasion, advanced BCLC stage, and poor survival of HCC patients. Functional experiments showed that GIHCG promotes HCC cells proliferation, migration, and invasion in vitro, and promotes xenografts growth and metastasis in vivo. Mechanistically, we demonstrated that GIHCG physically associates with EZH2 and the promoter of miR-200b/a/429, recruits EZH2 and DNMT1 to the miR-200b/a/429 promoter regions, upregulates histone H3K27 trimethylation and DNA methylation levels on the miR-200b/a/429 promoter, and dramatically silences miR-200b/a/429 expression. Furthermore, the biological functions of GIHCG on HCC are dependent on the silencing of miR-200b/a/429. Collectively, our results demonstrated the roles and functional mechanisms of GIHCG in HCC, and indicated GIHCG may act as a prognostic biomarker and potential therapeutic target for HCC.

Key Message

  • lncRNA-GIHCG is upregulated in HCC and associated with poor survival of patients.

  • GIHCG significantly promotes tumor growth and metastasis of HCC.

  • GIHCG physically associates with EZH2.

  • GIHCG upregulates H3K27me3 and DNA methylation levels on the miR-200b/a/429 promoter.

  • GIHCG epigenetically silences miR-200b/a/429 expression.

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    Authors and Affiliations

    1. Department of Special Medical Care I and Liver Transplantation, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China

      Cheng-jun Sui, Wei-feng Shen, Bing-hua Dai, Jiong-jiong Lu, Min-feng Zhang & Jia-mei Yang

    2. Department of Hepatobiliary & Pancreatovascular Surgery, First affiliated Hospital of Xiamen University, Xiamen, 361003, China

      Yan-ming Zhou

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    1. Cheng-jun Sui
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    Cheng-jun Sui and Yan-ming Zhou contributed equally to this work.

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    Sui, Cj., Zhou, Ym., Shen, Wf. et al. Long noncoding RNA GIHCG promotes hepatocellular carcinoma progression through epigenetically regulating miR-200b/a/429. J Mol Med 94, 1281–1296 (2016). https://doi.org/10.1007/s00109-016-1442-z

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