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.
Highlights
Hepatocellular carcinoma (HCC), presented with high morbidity and mortality, is the third leading cause of cancer-related deaths worldwide [1,2,3]
We found that fucoidan increased miR-29b to suppress the DNMT3B, which resulted in the upregulation of Metastasis Suppressor 1 (MTSS1)
Our results demonstrate the profound effect of fucoidan on the regulation of miR-29b-DNMT3B-MTSS1 axis and on the inhibition of TGF-β signaling in hepatocellular carcinoma (HCC) cells
Summary
Hepatocellular carcinoma (HCC), presented with high morbidity and mortality, is the third leading cause of cancer-related deaths worldwide [1,2,3]. In Taiwan, HCC is ranked second leading cause of cancer death due to its high recurrence after resection and poor prognosis [4], which is primarily related to tumor invasion and distant metastasis [5]. A tyrosine kinase inhibitor (TKI), is the only available agent to treat advanced HCC so far; the outcome remains poor due to the toxicity and salvage signaling pathway developing after TKI treatment [6,7]. MicroRNAs (miRs) have been demonstrated to play a crucial role in tumorigenesis and metastasis, suggesting that targeting miRNAs could be a promising approach for the treatment of human cancers [9,10]. MiRs are a class of endogenous, small, non-coding regulatory
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