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Mar Drugs. 2015 Sep 24;13(10):6099-116. doi: 10.3390/md13106099.

Fucoidan Elevates MicroRNA-29b to Regulate DNMT3B-MTSS1 Axis and Inhibit EMT in Human Hepatocellular Carcinoma Cells.

Yan MD1, Yao CJ2,3,4, Chow JM5,6, Chang CL6, Hwang PA7, Chuang SE8, Whang-Peng J9,10, Lai GM11,12,13,14,15.

Author information

1
Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan. yanmd717@gmail.com.
2
Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan. chow0803@yahoo.com.tw.
3
Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan. chow0803@yahoo.com.tw.
4
Comprehensive Cancer Center, Taipei Medical University, Taipei 11031, Taiwan. chow0803@yahoo.com.tw.
5
Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan. 101255@w.tmu.edu.tw.
6
Division of Hematology and Medical Oncology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan. 101255@w.tmu.edu.tw.
7
Seafood Technology Division, Fisheries Research Institute, Council of Agriculture, Keelung 20246, Taiwan. ampere0808@msn.com.
8
National Institute of Cancer Research, National Health Research Institutes, Miaoli County 35053, Taiwan. sechuang@nhri.org.tw.
9
Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan.
10
Comprehensive Cancer Center, Taipei Medical University, Taipei 11031, Taiwan.
11
Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan. gminlai@nhri.org.tw.
12
Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan. gminlai@nhri.org.tw.
13
Comprehensive Cancer Center, Taipei Medical University, Taipei 11031, Taiwan. gminlai@nhri.org.tw.
14
Division of Hematology and Medical Oncology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan. gminlai@nhri.org.tw.
15
National Institute of Cancer Research, National Health Research Institutes, Miaoli County 35053, Taiwan. gminlai@nhri.org.tw.

Abstract

Accumulating evidence has revealed that fucoidan exhibits anti-tumor activities by arresting cell cycle and inducing apoptosis in many types of cancer cells including hepatocellular carcinoma (HCC). Exploring its effect on microRNA expression, we found that fucoidan markedly upregulated miR-29b of human HCC cells. The induction of miR-29b was accompanied with suppression of its downstream target DNMT3B in a dose-dependent manner. The reduction of luciferase activity of DNMT3B 3'-UTR reporter by fucoidan was as markedly as that by miR-29b mimic, indicating that fucoidan induced miR-29b to suppress DNMT3B. Accordingly, the mRNA and protein levels of MTSS1 (metastasis suppressor 1), a target silenced by DNMT3B, were increased after fucoidan treatment. Furthermore, fucoidan also down-regulated TGF-β receptor and Smad signaling of HCC cells. All these effects leaded to the inhibition of EMT (increased E-cadherin and decreased N-cadherin) and prevention of extracellular matrix degradation (increased TIMP-1 and decreased MMP2, 9), by which the invasion activity of HCC cells was diminished. Our results demonstrate the profound effect of fucoidan not only on the regulation of miR-29b-DNMT3B-MTSS1 axis but also on the inhibition of TGF-β signaling in HCC cells, suggesting the potential of using fucoidan as integrative therapeutics against invasion and metastasis of HCC.

KEYWORDS:

DNMT3B; EMT; MTSS1; fucoidan; hepatocellular carcinoma; miR-29b

PMID:
26404322
PMCID:
PMC4626681
DOI:
10.3390/md13106099
[Indexed for MEDLINE]
Free PMC Article

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