title: The miR-200b-ZEB1 circuit regulates diverse stemness of human hepatocellular carcinoma.
abstract: Accumulating evidence suggests that human hepatocellular carcinoma (HCC) can be derived from cancer stem cells (CSCs), which contribute to tumor initiation, metastasis, chemoresistance, and recurrence. A great variety of HCC CSCs resulting in diverse clinical manifestations have been reported. However, how CSC diversity is regulated and generated remains unclear. Here we report that the miR-200b-ZEB1 circuit is closely involved with the induction and maintenance of a diverse group of CSCs. We found that miR-200b downregulation occurred in early HCC and associated with poor prognosis. The downregulation was attributable to genome deletion and promoter methylation of the miR-200a/b/429 gene. Ectopic expression of miR-200b or silencing of ZEB1 led to a decrease in CD13+and CD24+HCC CSCs and an increase in EpCAM+HCC CSCs. Mechanistically, miR-200b directly suppressed BMI1 and ZEB1 expressions. ZEB1 recognized promoters of CD13, CD24, and EpCAM genes resulting in CD13 and CD24 upregulation and EpCAM downregulation. Neither miR-200b nor ZEB1 had obvious effects on CD133 or CD90 expression. Silencing CD13 or CD24 expression suppressed tumorigenicity of HCC cells. Ectopic expression of CD24 reversed the suppression of tumorigenicity by ectopic expression of miR-200b. Clinically, miR-200b downregulation was coupled with ZEB1 upregulation in approximately two-thirds of HCC patients. ZEB1 expression was positively correlated with CD13 and CD24 expressions in HCCs, while miR-200b expression was positively correlated with EpCAM. Our findings suggest that the miR-200b-ZEB1 circuit is a master regulator of diverse stemness of HCC, which differentiates HCCs into those containing CD13+/CD24+CSCs from those containing EpCAM+CSCs.
authors.affiliation: Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan.
authors.forename: Shu-Chun
authors.initials: SC
authors.lastname: Tsai
authors.affiliation: Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan.
authors.forename: Chen-Chun
authors.initials: CC
authors.lastname: Lin
authors.affiliation: Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan.|Department of Biochemistry and Molecular Medicine, University of California Davis, Sacramento, California.
authors.forename: Tsung-Chieh
authors.initials: TC
authors.lastname: Shih
authors.affiliation: Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan.
authors.forename: Rong-Jeng
authors.initials: RJ
authors.lastname: Tseng
authors.affiliation: Department of General Surgery, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan.
authors.forename: Ming-Chin
authors.initials: MC
authors.lastname: Yu
authors.affiliation: Medical Statistics and Clinical Informatics Lab, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Yu-Jr
authors.initials: YJ
authors.lastname: Lin
authors.affiliation: Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan.|College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Sen-Yung
authors.identifier: 0000-0002-1723-7261
authors.initials: SY
authors.lastname: Hsieh
mesh_terms: D000943:Antigens, Differentiation / Q000378:metabolism; D018826:CD13 Antigens / Q000378:metabolism; D051927:CD24 Antigen / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000378:metabolism; D015536:Down-Regulation; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000382:microbiology; D011401:Promoter Regions, Genetic; D000071799:Zinc Finger E-box-Binding Homeobox 1 / Q000378:metabolism*
chemical_list: D000943:Antigens, Differentiation; D051927:CD24 Antigen; D004273:DNA, Neoplasm; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; D018826:CD13 Antigens
keywords: CD24; ZEB1; cancer stem cells; hepatoma; miR-200b; microRNA