title: DDX3 Represses Stemness by Epigenetically Modulating Tumor-suppressive miRNAs in Hepatocellular Carcinoma.
abstract: 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.
authors.affiliation: Institute of Biochemistry and Molecular Biology, School of Life Sciences, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Hao-Kang
authors.initials: HK
authors.lastname: Li
authors.affiliation: Institute of Biochemistry and Molecular Biology, School of Life Sciences, National Yang-Ming University, Taipei, Taiwan.|Department of Biological Science and Technology, College of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan.
authors.forename: Ru-Tsun
authors.initials: RT
authors.lastname: Mai
authors.affiliation: Department of Biological Science and Technology, College of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan.|Institute of Bioinformatics and Systems Biology, College of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan.
authors.forename: Hsien-Da
authors.initials: HD
authors.lastname: Huang
authors.affiliation: Department of Biological Science and Technology, College of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan.|Institute of Bioinformatics and Systems Biology, College of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan.
authors.forename: Chih-Hung
authors.initials: CH
authors.lastname: Chou
authors.affiliation: Department of Biological Science and Technology, College of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan.|Department of Medical Research, Mackay Memorial Hospital, Hsinchu, Taiwan.
authors.forename: Yi-An
authors.initials: YA
authors.lastname: Chang
authors.affiliation: Institute of Biochemistry and Molecular Biology, School of Life Sciences, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Yao-Wen
authors.initials: YW
authors.lastname: Chang
authors.affiliation: Institute of Biochemistry and Molecular Biology, School of Life Sciences, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Li-Ru
authors.initials: LR
authors.lastname: You
authors.affiliation: Department of Life Sciences and Institute of Genome Sciences, School of Life Sciences, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Chun-Ming
authors.initials: CM
authors.lastname: Chen
authors.affiliation: Institute of Biochemistry and Molecular Biology, School of Life Sciences, National Yang-Ming University, Taipei, Taiwan.|Department of Biological Science and Technology, College of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan.
authors.forename: Yan-Hwa Wu
authors.initials: YH
authors.lastname: Lee
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D053487:DEAD-box RNA Helicases / Q000096:biosynthesis* / Q000235:genetics; D000090205:DNA Methyltransferase 3A; D044127:Epigenesis, Genetic; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000201:enzymology* / Q000473:pathology
chemical_list: C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse; D009363:Neoplasm Proteins; D000090205:DNA Methyltransferase 3A; C119332:DDX3X protein, human; D053487:DEAD-box RNA Helicases