title: Overexpression of ZFX confers self-renewal and chemoresistance properties in hepatocellular carcinoma.
abstract: Zinc finger protein X-linked (ZFX) is a zinc finger protein of Zfy family, which is highly conserved in vertebrates. This transcriptional regulator is not only highly expressed in embryonic stem cells (ESC) and hematopoietic stem cells, but is also upregulated in a number of human cancers where it is functional related to cell proliferation and survival. Hepatocellular carcinoma (HCC) is highly aggressive cancer that commonly resistant to most chemotherapies and displays stemness characteristics. In this study, we examined the expression of ZFX in HCC and its possible functional implications in liver tumorigenesis. Quantitative RT-PCR analysis showed common overexpressions of ZFX in 51.8% HCC tumors when compared with their adjacent nonmalignant liver (n = 43/83; p = 0.004). Inline with the pluripotency role of ZFX, we found silencing of ZFX readily inhibited self-renewal capability (p = 0.0022), colony formation ability (p < 0.0001) and cell proliferation (p < 0.0001) through G0/G1 cell cycle arrest of HCC cells (p = 0.0038). In addition, suppression of ZFX sensitized HCC cells to chemotherapeutic agent cisplatin (p < 0.0001). Further investigations suggested that ZFX bind on the promoter of two important mediators, namely Nanog and SOX-2, activating their expressions in HCC (p < 0.0001). Moreover, in vivo xenograft study demonstrated that overexpression of ZFX would promote the tumor growth (p = 0.031). Taken together, our results show, for the first time, commonly overexpressions of ZFX in HCC, where it likely contributes to the stemness and pluripotent behavior of this highly malignant cancer.
authors.affiliation: Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, Hong Kong, China.
authors.forename: Keng Po
authors.initials: KP
authors.lastname: Lai
authors.forename: Jiawei
authors.initials: J
authors.lastname: Chen
authors.forename: Mian
authors.initials: M
authors.lastname: He
authors.forename: Arthur K K
authors.initials: AK
authors.lastname: Ching
authors.forename: Coleen
authors.initials: C
authors.lastname: Lau
authors.forename: Paul B S
authors.initials: PB
authors.lastname: Lai
authors.forename: Ka-Fai
authors.initials: KF
authors.lastname: To
authors.forename: Nathalie
authors.initials: N
authors.lastname: Wong
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D059585:G1 Phase Cell Cycle Checkpoints; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D000071317:Nanog Homeobox Protein; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism; D010455:Peptides; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism; D047368:Tumor Burden
chemical_list: D000970:Antineoplastic Agents; D018398:Homeodomain Proteins; D051741:Kruppel-Like Transcription Factors; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D010455:Peptides; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; C062076:zinc finger protein, X-linked; C085032:IC 101; D002945:Cisplatin
keywords: ZFX; chemoresistance; hepatocellular carcinoma; self-renewal