Dysregulated expression of stem cell factor Bmi1 in precancerous lesions of the gastrointestinal tract.
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.
Tateishi
Keisuke
K
Department of Gastroenterology, University of Tokyo, Japan. ktate-tky@umin.ac.jp
Ohta
Miki
M
Kanai
Fumihiko
F
Guleng
Bayasi
B
Tanaka
Yasuo
Y
Asaoka
Yoshinari
Y
Tada
Motohisa
M
Seto
Motoko
M
Jazag
Amarsanaa
A
Lianjie
Lin
L
Okamoto
Makoto
M
Isayama
Hiroyuki
H
Tada
Minoru
M
Yoshida
Haruhiko
H
Kawabe
Takao
T
Omata
Masao
M
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
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