title: Activation of the ATF6, XBP1 and grp78 genes in human hepatocellular carcinoma: a possible involvement of the ER stress pathway in hepatocarcinogenesis.
abstract: OBJECTIVE
  We identified the glucose-regulated protein (grp) 78 as a transformation-associated gene in hepatocellular carcinoma (HCC). Grp78 is a molecular chaperone involved in the unfolded protein response, the expression of which can be regulated by the transcription factors ATF6 and XBP1. Thus, we investigated the regulatory mechanisms of the grp78 gene in liver malignancy.
  
  
  METHODS
  Expression of grp78, ATF6 and XBP1 was examined by Northern blot, RT-PCR, immunoblot and immunohistochemical analyses. A reporter assay of the grp78 promoter was also performed.
  
  
  RESULTS
  Elevation of grp78 and ATF6 mRNAs and the splicing of XBP1 mRNA, resulting in the activation of XBP1 product, occurred in HCC tissues with increased histological grading. Higher accumulation of the grp78 product in the cytoplasm, concomitantly with marked nuclear localization of the activated ATF6 product (p50ATF6), was observed in moderately to poorly differentiated HCC tissues. Cooperation between the distal DNA segment and the proximal endoplasmic reticulum stress response elements was essential for maximum transcription of the grp78 promoter in HCC cells.
  
  
  CONCLUSIONS
  The endoplasmic reticulum stress pathway mediated by ATF6 and by IRE1-XBP1 systems seems essential for the transformation-associated expression of the grp78 gene in HCCs.
authors.affiliation: Department of Microbiology and Cell Biology, The Tokyo Metropolitan Institute of Medical Science, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8613, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Shuda
authors.forename: Nobuo
authors.initials: N
authors.lastname: Kondoh
authors.forename: Nobuo
authors.initials: N
authors.lastname: Imazeki
authors.forename: Kenji
authors.initials: K
authors.lastname: Tanaka
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Okada
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Mori
authors.forename: Akiyuki
authors.initials: A
authors.lastname: Hada
authors.forename: Masaaki
authors.initials: M
authors.lastname: Arai
authors.forename: Toru
authors.initials: T
authors.lastname: Wakatsuki
authors.forename: Osamu
authors.initials: O
authors.lastname: Matsubara
authors.forename: Naoki
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Mikio
authors.initials: M
authors.lastname: Yamamoto
mesh_terms: D051702:Activating Transcription Factor 6; D000328:Adult; D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000503:physiopathology* / Q000601:surgery; D002352:Carrier Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics*; D004721:Endoplasmic Reticulum / Q000502:physiology; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006360:Heat-Shock Proteins; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000503:physiopathology* / Q000601:surgery; D008297:Male; D008875:Middle Aged; D018832:Molecular Chaperones / Q000235:genetics*; D011401:Promoter Regions, Genetic; D012326:RNA Splicing; D012333:RNA, Messenger / Q000032:analysis; D000071701:Regulatory Factor X Transcription Factors; D013312:Stress, Physiological / Q000503:physiopathology; D014157:Transcription Factors / Q000235:genetics*; D000071717:X-Box Binding Protein 1
chemical_list: C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D012333:RNA, Messenger; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human