title: RPN2-mediated glycosylation of tetraspanin CD63 regulates breast cancer cell malignancy.
abstract: BACKGROUND
  The tetraspanin CD63 is a highly N-glycosylated protein that is known to regulate cancer malignancy. However, the contribution of glycosylation of CD63 to cancer malignancy remains unclear. Previously, we reported that ribophorin II (RPN2), which is part of an N-oligosaccharyle transferase complex, is responsible for drug resistance in breast cancer cells. In this study, we demonstrate that cancer malignancy associated with the glycosylation of CD63 is regulated by RPN2.
  
  
  RESULTS
  Inhibition of RPN2 expression led to a reduction in CD63 glycosylation. In addition, the localization of CD63 was deregulated by knockdown of RPN2. Interestingly, multidrug resistance protein 1 (MDR1) localization was displaced from the cell surface in CD63-silenced cells. CD63 silencing reduced the chemoresistance and invasion ability of malignant breast cancer cells. Furthermore, the enrichment of CD63/MDR1-double positive cells was associated with lymph node metastasis. Taken together, these results indicated that high glycosylation of CD63 by RPN2 is implicated in clinical outcomes in breast cancer patients.
  
  
  CONCLUSIONS
  These findings describe a novel and important function of RPN2-mediated CD63 glycosylation, which regulates MDR1 localization and cancer malignancy, including drug resistance and invasion.
authors.forename: Naoomi
authors.initials: N
authors.lastname: Tominaga
authors.forename: Keitaro
authors.initials: K
authors.lastname: Hagiwara
authors.forename: Nobuyoshi
authors.initials: N
authors.lastname: Kosaka
authors.forename: Kimi
authors.initials: K
authors.lastname: Honma
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Nakagama
authors.affiliation: Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan. tochiya@ncc.go.jp.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ochiya
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D006031:Glycosylation; D006602:Hexosyltransferases; D006801:Humans; D008207:Lymphatic Metastasis / Q000473:pathology; D061986:MCF-7 Cells; D008565:Membrane Proteins / Q000008:administration & dosage; D008875:Middle Aged; D009367:Neoplasm Staging; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D060149:Tetraspanin 30 / Q000235:genetics / Q000378:metabolism*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; C554586:CD63 protein, human; D008565:Membrane Proteins; D060149:Tetraspanin 30; C034241:ribophorin; D006602:Hexosyltransferases; C517590:RPN2 protein, human; D046988:Proteasome Endopeptidase Complex