title: Loss ofN-Acetylgalactosaminyltransferase-4 Orchestrates Oncogenic MicroRNA-9 in Hepatocellular Carcinoma.
abstract: Deregulated expression ofN-acetylgalactosaminyltransferases (GALNTs), which is responsible for the initial step of mucin-typeO-glycosylation, could produce abnormal truncatedO-glycans and thereby exert pivotal functions during malignant transformation. GALNT4 is one of the few isoforms preferring to catalyze partial GalNAc-glycosylated substrates and modify the sites not utilized by other known GALNTs. This study aims to evaluate the impact of GALNT4 expression on malignant transformation of hepatocellular carcinoma (HCC). Immunohistochemistry andin situhybridization analysis were performed to assess GALNT4 and miR-9 level in clinical specimens, respectively. GALNT4 expression is markedly repressed in primary HCC tissues, and reduced expression of GALNT4 is significantly associated with adverse survival of patients with HCC. Functional investigations demonstrate that repressed GALNT4 could promote migration, invasion, anoikis resistance, and stemness of HCC cellsin vitroas well as tumor growthin vivoThe wild-type GALNT4 could modifyO-linked glycosylation on EGFR and thus modulate the activity of EGFR. A luciferase activity assay further identified microRNA-9 (miR-9) as the crucial specific arbitrator for GALNT4 expression in HCC cells. Furthermore, restoring GALNT4 expression attenuates miR-9-mediated oncogenic functions. Kaplan-Meier survival analysis indicates that the miR-9/GALNT4 expression signature yields promising prognostic significance to refine the risk stratification of patients with HCC. In conclusion, this study establishes the miR-9/GALNT4 axis as a potential adverse prognostic factor and therapeutic target for HCC patients.
authors.affiliation: Departments of Biochemistry and Molecular Biology.
authors.forename: Yidong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200032, China.
authors.forename: Haiou
authors.initials: H
authors.lastname: Liu
authors.affiliation: Departments of Biochemistry and Molecular Biology.
authors.forename: Liu
authors.initials: L
authors.lastname: Yang
authors.affiliation: Departments of Biochemistry and Molecular Biology.
authors.forename: Qian
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Departments of Biochemistry and Molecular Biology.
authors.forename: Weisi
authors.initials: W
authors.lastname: Liu
authors.affiliation: Departments of Biochemistry and Molecular Biology.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Fu
authors.affiliation: Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
authors.forename: Weijuan
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Departments of Biochemistry and Molecular Biology.
authors.forename: Haijian
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Departments of Biochemistry and Molecular Biology. Electronic address: jjxufdu@fudan.edu.cn.
authors.forename: Jiejie
authors.initials: J
authors.lastname: Xu
authors.affiliation: Departments of Biochemistry and Molecular Biology. Electronic address: jxgu@shmu.edu.cn.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Gu
mesh_terms: D000328:Adult; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008113:Liver Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D017350:N-Acetylgalactosaminyltransferases / Q000235:genetics*; D009361:Neoplasm Invasiveness / Q000175:diagnosis / Q000235:genetics / Q000473:pathology; D011379:Prognosis; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D000097763:Polypeptide N-acetylgalactosaminyltransferase
chemical_list: D035683:MicroRNAs; D017350:N-Acetylgalactosaminyltransferases; D034741:RNA, Small Interfering; D000097763:Polypeptide N-acetylgalactosaminyltransferase; C541874:MIRN92 microRNA, human
keywords: GALNT4; Prognostic biomarker; anoikis; glycobiology; glycosyltransferase; hepatocellular carcinoma; microRNA (miRNA); microRNA-9; migration; post-transcriptional regulation