title: N-glycan alterations are associated with drug resistance in human hepatocellular carcinoma.
abstract: BACKGROUND
  Correlations of disease phenotypes with glycosylation changes have been analysed intensively in the tumor biology field. Glycoforms potentially associated with carcinogenesis, tumor progression and cancer metastasis have been identified. In cancer therapy, drug resistance is a severe problem, reducing therapeutic effect of drugs and adding to patient suffering. Although multiple mechanisms likely underlie resistance of cancer cells to anticancer drugs, including overexpression of transporters, the relationship of glycans to drug resistance is not well understood.
  
  
  RESULTS
  We established epirubicin (EPI)--and mitoxantrone (MIT)--resistant cell lines (HLE-EPI and HLE-MIT) from the human hepatocellular carcinoma cell line (HLE). HLE-EPI and HLE-MIT overexpressed transporters MDR1/ABCB1 and BCRP/ABCG2, respectively. Here we compared the glycomics of HLE-EPI and HLE-MIT cells with the parental HLE line. Core fucosylated triantennary oligosaccharides were increased in the two resistant lines. We investigated mRNA levels of glycosyltransferases synthesizing this oligosaccharide, namely, N-acetylglucosaminyltransferase (GnT)-IVa, GnT-IVb and alpha1,6-fucosyltransferase (alpha1,6-FucT), and found that alpha1,6-FucT was particularly overexpressed in HLE-MIT cells. In HLE-EPI cells, GnT-IVa expression was decreased, while GnT-IVb was increased. Both GnT-IVs were downregulated in HLE-MIT cells. HLE-MIT cells also showed decreases in fucosylated tetraantennary oligosaccharide, the product of GnT-V. GnT-V expression was decreased in both lines, but particularly so in HLE-MIT cells. Thus both N-glycan and glycosyltransferase expression was altered as cells acquired tolerance, suggesting novel mechanisms of drug resistance.
  
  
  CONCLUSIONS
  N-glycan and glycosyltransferase expression in HLE-EPI and HLE-MIT were analysed and presented that glycans altered according with acquired tolerance. These results suggested novel mechanisms of drug resistance.
authors.affiliation: Department of General Surgery, Graduate School of Medicine, Hokkaido University, Japan. shibe@poem.ocn.ne.jp
authors.forename: Takeaki
authors.initials: T
authors.lastname: Kudo
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Nakagawa
authors.forename: Masato
authors.initials: M
authors.lastname: Takahashi
authors.forename: Jun
authors.initials: J
authors.lastname: Hamaguchi
authors.forename: Naoya
authors.initials: N
authors.lastname: Kamiyama
authors.forename: Hideki
authors.initials: H
authors.lastname: Yokoo
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Nakanishi
authors.forename: Takahito
authors.initials: T
authors.lastname: Nakagawa
authors.forename: Toshiya
authors.initials: T
authors.lastname: Kamiyama
authors.forename: Kisaburo
authors.initials: K
authors.lastname: Deguchi
authors.forename: Shin-Ichiro
authors.initials: S
authors.lastname: Nishimura
authors.forename: Satoru
authors.initials: S
authors.lastname: Todo
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D002240:Carbohydrate Sequence; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism*; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D004361:Drug Tolerance; D015251:Epirubicin / Q000494:pharmacology; D005647:Fucosyltransferases / Q000378:metabolism; D006031:Glycosylation; D016695:Glycosyltransferases / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D008942:Mitoxantrone / Q000494:pharmacology; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism; D025942:Oligosaccharides, Branched-Chain / Q000737:chemistry / Q000378:metabolism; D011134:Polysaccharides / Q000737:chemistry / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: D000903:Antibiotics, Antineoplastic; D025942:Oligosaccharides, Branched-Chain; D011134:Polysaccharides; D015251:Epirubicin; D008942:Mitoxantrone; D016695:Glycosyltransferases; D005647:Fucosyltransferases; D017351:N-Acetylglucosaminyltransferases; C037649:N-acetyllactosaminide beta-1,6-N-acetylglucosaminyltransferase