title: CEACAM1 long cytoplasmic domain isoform is associated with invasion and recurrence of hepatocellular carcinoma.
abstract: BACKGROUND
  The two isoforms of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), 1 with a long cytoplasmic domain (CEACAM1-L) and 1 with a short (CEACAM1-S), are involved in different signaling pathways. β2-spectrin (β2SP) is an adaptor protein that plays critical roles in the proper control of Smad access to activate receptors involved in regulation of TGF-β signaling. In this study, we examined the association between CEACAM1 isoform balance and hepatocellular carcinoma (HCC) malignant potential and investigated the possibility of a molecular interaction between CEACAM1 and β2SP.
  
  
  METHODS
  Immunohistochemical analysis was carried out with CEACAM1-L or CEACAM1-S antibodies on 154 HCC tissues to correlate with the factors of malignancy. Invasion assay was performed for the effect of CEACAM1 expression on HCC cell lines. Moreover, immunohistochemical analysis and immunoprecipitation analysis were performed to investigate the association between CEACAM1 isoform balance and β2SP.
  
  
  RESULTS
  In immunohistochemical analysis, CEACAM1-L expression dominance was a risk factor for HCC recurrence (p = 0.04) and was significantly associated with a shorter survival compared with CEACAM1-S expression dominance. Invasion assay indicated that CEACAM1-4L-transfected HLF and PLC/PRF/5 cells showed significantly increased invasion (p < 0.0001) and CEACAM1-4S-transfected HLF cells showed significantly decreased invasion. Immunohistochemical analysis of β2SP suggested that the HCCs with CEACAM1-L-dominant expression were more strongly stained with β2SP than the HCCs with CEACAM1-S-dominant expression (p = 0.013), and coprecipitation assays indicated that CEACAM1-L could bind to β2SP.
  
  
  CONCLUSIONS
  CEACAM1-L may enhance the HCC invasiveness through an interaction with β2SP and subsequent effects on TGF-β signaling.
authors.affiliation: Second Department of Surgery, School of Medicine, Wakayama Medical University, Wakayama, Japan.
authors.forename: Shigehisa
authors.initials: S
authors.lastname: Kiriyama
authors.forename: Shozo
authors.initials: S
authors.lastname: Yokoyama
authors.forename: Masaki
authors.initials: M
authors.lastname: Ueno
authors.forename: Shinya
authors.initials: S
authors.lastname: Hayami
authors.forename: Junji
authors.initials: J
authors.lastname: Ieda
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Yamaguchi
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Mitani
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Masaji
authors.initials: M
authors.lastname: Tani
authors.forename: Lopa
authors.initials: L
authors.lastname: Mishra
authors.forename: John E
authors.initials: JE
authors.lastname: Shively
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yamaue
mesh_terms: D000368:Aged; D015703:Antigens, CD / Q000032:analysis* / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000737:chemistry* / Q000235:genetics / Q000473:pathology*; D015815:Cell Adhesion Molecules / Q000032:analysis* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000737:chemistry* / Q000235:genetics / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local / Q000737:chemistry*; D020033:Protein Isoforms / Q000032:analysis; D012189:Retrospective Studies; D015398:Signal Transduction; D051900:Smad3 Protein / Q000378:metabolism; D013049:Spectrin / Q000032:analysis* / Q000378:metabolism; D015996:Survival Rate; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D015703:Antigens, CD; C069847:CD66 antigens; D015815:Cell Adhesion Molecules; D020033:Protein Isoforms; C452439:SPTBN1 protein, human; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D013049:Spectrin