標題: DDX3 Represses Stemness by Epigenetically Modulating Tumor-suppressive miRNAs in Hepatocellular Carcinoma
作者: Li, Hao-Kang
Mai, Ru-Tsun
Huang, Hsien-Da
Chou, Chih-Hung
Chang, Yi-An
Chang, Yao-Wen
You, Li-Ru
Chen, Chun-Ming
Lee, Yan-Hwa Wu
生物科技學院
生醫工程研究所
College of Biological Science and Technology
Institute of Biomedical Engineering
公開日期: 27-Jun-2016
摘要: Studies indicate that the presence of cancer stem cells (CSCs) is responsible for poor prognosis of hepatocellular carcinoma (HCC) patients. In this study, the functional role of DDX3 in regulation of hepatic CSCs was investigated. Our results demonstrated that reduced DDX3 expression was not only inversely associated with tumor grade, but also predicted poor prognosis of HCC patients. Knockdown of DDX3 in HCC cell line HepG2 induced stemness gene signature followed by occurrence of self-renewal, chemoreisistance, EMT, migration as well as CSC expansion, and most importantly, DDX3 knockdown promotes tumorigenesis. Moreover, we found positive correlations between DDX3 level and expressions of tumor-suppressive miR-200b, miR-200c, miR-122 and miR-145, but not miR-10b and miR-519a, implying their involvement in DDX3 knockdown-induced CSC phenotypes. In addition, DDX3 reduction promoted up-regulation of DNA methyltransferase 3A (DNMT3A), while neither DNMT3B nor DNMT1 expression was affected. Enriched DNMT3A binding along with hypermethylation on promoters of these tumor-suppressive miRNAs reflected their transcriptional repressions in DDX3-knockdown cells. Furthermore, individual restoration of these tumor-suppressive miRNAs represses DDX3 knockdown-induced CSC phenotypes. In conclusion, our study suggested that DDX3 prevents generation of CSCs through epigenetically regulating a subset of tumor-suppressive miRNAs expressions, which strengthens tumor suppressor role of DDX3 in HCC.
URI: http://dx.doi.org/10.1038/srep28637
http://hdl.handle.net/11536/133918
ISSN: 2045-2322
DOI: 10.1038/srep28637
期刊: SCIENTIFIC REPORTS
Volume: 6
起始頁: 0
結束頁: 0
Appears in Collections:Articles


Files in This Item:

  1. aae757b24bd9d26551235206efde4300.pdf