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Epigenetic modification of MiR-429 promotes liver tumour-initiating cell properties by targeting Rb binding protein 4
  1. Liang Li1,2,
  2. Jing Tang1,2,
  3. Baohua Zhang3,
  4. Wen Yang1,2,
  5. Miyang LiuGao1,2,
  6. Ruoyu Wang1,
  7. Yexiong Tan1,2,
  8. Jianling Fan1,4,
  9. Yanxin Chang1,
  10. Jing Fu1,2,
  11. Feng Jiang1,
  12. Caiyang Chen1,
  13. Yingcheng Yang1,2,
  14. Jin Gu5,
  15. Dingming Wu5,
  16. Linna Guo1,2,
  17. Dan Cao1,2,
  18. Hengyu Li1,
  19. Guangwen Cao6,
  20. Mengchao Wu3,
  21. Michael Q Zhang5,
  22. Lei Chen1,2,
  23. Hongyang Wang1,2,7
  1. 1International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China
  2. 2National Center for Liver Cancer, Shanghai, China
  3. 3Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
  4. 4Changzheng Hospital, Second Military Medical University, Shanghai, China
  5. 5Bioinformatics Division, TNLIST/Department of Automation, Tsinghua University, Beijing, China
  6. 6Department of Epidemiology, Second Military Medical University, Shanghai, China
  7. 7National Laboratory for Oncogenes and Related Genes, Cancer Institute, Ruijing Hospital, Shanghai Jiao Tong University, Shanghai, China
  1. Correspondence to Dr Hongyang Wang, International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, 225 Changhai Road, Shanghai 200438, China; hywangk{at}vip.sina.com and Dr Lei Chen, International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, 225 Changhai Road, Shanghai 200438, China; Chenlei@smmu.edu.cn

Abstract

Objective Liver tumour-initiating cells (T-ICs) are critical for hepatocarcinogenesis. However, the underlying mechanism regulating the function of liver T-ICs remains unclear.

Methods Tissue microarrays containing 242 hepatocellular carcinoma (HCC) samples were used for prognostic analysis. Magnetically activated cell sorting was used to isolate epithelial cell adhesion molecule (EPCAM)-positive cells. The gene expressions affected by miR-429 were determined by arrays. Co-immunoprecipitation was used to study interactions among retinoblastoma protein (RB1), Rb binding protein 4 (RBBP4) and E2F transcription factor 1 (E2F1). The DNA methylation status in CpG islands was detected by quantitative methylation analysis. miRNAs in microvesicles were isolated by a syringe filter system.

Results The significant prognosis factor miR-429 was upregulated in HCC tissues and also in primary liver T-ICs isolated from clinical samples. The enrichment of miR-429 in EPCAM+ T-ICs contributed to hepatocyte self-renewal, malignant proliferation, chemoresistance and tumorigenicity. A novel functional axis involving miR-429, RBBP4, E2F1 and POU class 5 homeobox 1 (POU5F1 or OCT4) governing the regulation of liver EPCAM+ T-ICs was established in vitro and in vivo. The molecular mechanism regulating miR-429 expression, involving four abnormal hypomethylated sites upstream of the miR-200b/miR-200a/miR-429 cluster, was first defined in both EPCAM+ liver T-ICs and very early-stage HCC tissues. miR-429 secreted by high-expressing cells has the potential to become a proactive signalling molecule to mediate intercellular communication.

Conclusions Epigenetic modification of miR-429 can manipulate liver T-ICs by targeting the RBBP4/E2F1/OCT4 axis. This miRNA might be targeted to inactivate T-ICs, thus providing a novel strategy for HCC prevention and treatment.

  • Hepatocellular Carcinoma
  • Stem Cells
  • Signal Transduction

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