title: Dysregulated expression of stem cell factor Bmi1 in precancerous lesions of the gastrointestinal tract.
abstract: OBJECTIVE
  It is important to identify the definitive molecular switches involved in the malignant transformation of premalignant tissues. Cellular senescence is a specific characteristic of precancerous tissues, but not of cancers, which might reflect tumorigenesis-protecting mechanisms in premalignant lesions. Polycomb protein Bmi1, which is a potent negative regulator of the p16INK4 gene, suppresses senescence in primary cells and is overexpressed in various cancers. We hypothesized that Bmi1 expression would also be dysregulated in precancerous lesions in human digestive precancerous tissues.
  
  
  METHODS
  Bmi1 expression was investigated in cancerous and precancerous tissues of the digestive tract. The expression of p16, beta-catenin, and Gli1 and the in vivo methylation status of the p16 gene were also analyzed in serial sections of colonic precancerous lesions.
  
  
  RESULTS
  Bmi1 was clearly overexpressed across a broad spectrum of gastrointestinal cancers, and the expression of Bmi1 increased in a manner that reflected the pathologic malignant features of precancerous colonic tissues (low-grade dysplasia, 12.9 +/- 2.0%; high-grade dysplasia, 82.9 +/- 1.6%; cancer, 87.5 +/- 2.4%). p16 was also strongly expressed in high-grade dysplasia, but not in cancers. p16 promoter methylation was detected only in some Bmi1-positive neoplastic cells.
  
  
  CONCLUSIONS
  Bmi1 overexpression was correlated with the malignant grades of human digestive precancerous tissues, which suggests that advanced Bmi1 dysregulation might predict malignant progression. The abnormal Bmi1 expression might link to malignant transformation via the disturbance of orderly histone modification.
authors.affiliation: Department of Gastroenterology, University of Tokyo, Japan. ktate-tky@umin.ac.jp
authors.forename: Keisuke
authors.initials: K
authors.lastname: Tateishi
authors.forename: Miki
authors.initials: M
authors.lastname: Ohta
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Kanai
authors.forename: Bayasi
authors.initials: B
authors.lastname: Guleng
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Yoshinari
authors.initials: Y
authors.lastname: Asaoka
authors.forename: Motohisa
authors.initials: M
authors.lastname: Tada
authors.forename: Motoko
authors.initials: M
authors.lastname: Seto
authors.forename: Amarsanaa
authors.initials: A
authors.lastname: Jazag
authors.forename: Lin
authors.initials: L
authors.lastname: Lianjie
authors.forename: Makoto
authors.initials: M
authors.lastname: Okamoto
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Isayama
authors.forename: Minoru
authors.initials: M
authors.lastname: Tada
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Yoshida
authors.forename: Takao
authors.initials: T
authors.lastname: Kawabe
authors.forename: Masao
authors.initials: M
authors.lastname: Omata
mesh_terms: D045744:Cell Line, Tumor; D003106:Colon / Q000378:metabolism / Q000473:pathology; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D005770:Gastrointestinal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D041981:Gastrointestinal Tract / Q000378:metabolism / Q000473:pathology*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D063150:Polycomb Repressive Complex 1; D016133:Polymerase Chain Reaction / Q000379:methods; D011230:Precancerous Conditions / Q000235:genetics* / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D051153:Wnt Proteins / Q000378:metabolism
chemical_list: C069077:BMI1 protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D053823:Hedgehog Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; D051153:Wnt Proteins; D063150:Polycomb Repressive Complex 1