Insulin-like growth factor binding protein-related protein 1 (IGFBP-rP1) has potential tumour-suppressive activity in human lung cancer.
The expression of insulin-like growth factor binding protein-related protein 1 (IGFBP-rP1) is decreased in various tumours, but the role of IGFBP-rP1 in lung cancer is not yet clear. In this study, IGFBP-rP1 expression in lung cancer cell lines was evaluated and reduced expression of IGFBP-rP1 was found. In tissue microarrays containing 138 primary tumours and 20 normal lung tissues analysed by immunohistochemistry, 58 tumours (42%) exhibited no expression of IGFBP-rP1, while all 20 normal lung tissues showed high expression. In squamous cell lung cancer, low expression of IGFBP-rP1 was significantly linked to high-grade tumours. Treatment with 5-aza-2'-deoxycytidine restored the expression of IGFBP-rP1 in three of four lung cancer cell lines. Sequencing of PCR products of sodium bisulphite-treated genomic DNA from the three lung cancer cell lines revealed a heterogeneous methylation pattern in the region of exon 1 and intron 1. Stable transfection of IGFBP-rP1 full-length cDNA into the H2170 lung cancer cell line led to increased expression of IGFBP-rP1 protein. IGFBP-rP1-positive transfectants exhibited remarkably reduced colony-forming ability in soft agar, suppression of tumour growth rate in nude mice, and increased apoptotic cell number as well as activated caspase-3 expression level. The data suggest that IGFBP-rP1 is a tumour suppressor inactivated by DNA methylation in human lung cancer.
Chen
Y
Y
Institute of Pathology, University Hospital Charité, Schumannstr 20-21, D-10098 Berlin, Germany.
Pacyna-Gengelbach
M
M
Ye
F
F
Knösel
T
T
Lund
P
P
Deutschmann
N
N
Schlüns
K
K
Kotb
W F M A
WF
Sers
C
C
Yasumoto
H
H
Usui
T
T
Petersen
I
I
D000230:Adenocarcinoma / Q000737:chemistry / Q000235:genetics; D017209:Apoptosis / Q000502:physiology; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000737:chemistry / Q000235:genetics; D045744:Cell Line, Tumor; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors; D004273:DNA, Neoplasm / Q000235:genetics; D000077209:Decitabine; D004847:Epithelial Cells / Q000737:chemistry; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D018969:Insulin-Like Growth Factor Binding Proteins / Q000032:analysis*; D008168:Lung / Q000737:chemistry; D008175:Lung Neoplasms / Q000737:chemistry* / Q000235:genetics; D046228:Microarray Analysis / Q000379:methods; D009367:Neoplasm Staging; D014162:Transfection / Q000379:methods; D025521:Tumor Suppressor Proteins / Q000032:analysis*
D004273:DNA, Neoplasm; D018969:Insulin-Like Growth Factor Binding Proteins; D025521:Tumor Suppressor Proteins; C102529:insulin-like growth factor binding protein-related protein 1; D000077209:Decitabine; D015254:DNA Modification Methylases; D001374:Azacitidine