Frequent trefoil factor 3 (TFF3) overexpression and promoter hypomethylation in mouse and human hepatocellular carcinomas.
Expression profiling analysis revealed ectopic high expression of mouse TFF3 in non-tumor liver tissues from the hepatocellular carcinoma (HCC) susceptible PWK/Rbrc strain. TFF3 is a member of the trefoil factor family peptides, which are small secreted proteins regulating mucosal regeneration and repair, and which are overexpressed during inflammatory processes and cancer progression. We, therefore, analyzed the TFF3 expression extensively in mouse and human HCCs. Expression of the mouse TFF3 gene was significantly increased in 6 out of 7 HCCs from a PWK spontaneous tumor model and in all 7 HCCs from an SV40T antigen-induced transgenic MT-D2C57BL/6 model. In humans, 8 of 20 HCCs (40%) had overexpression of TFF3 in both mRNA level and protein level. We then analyzed DNA methylation patterns of the TFF3 promoter region to evaluate expression regulation of promoter methylation. In mouse HCCs, we demonstrated that two CpGs, at positions -992 and +109, were hypomethylated in 13 of 14 mouse HCCs. In human HCCs, hypomethylation at CpG -260 was associated with TFF3 overexpression (p=0.04). These results indicate that TFF3 overexpression may be a critical process in mouse and human hepatocellular carcinogenesis, and the specific promoter CpG hypomethylation may be one of the regulation mechanisms of TFF3 overexpression in HCCs.
Okada
Haruhiko
H
Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Kimura
Makoto T
MT
Tan
Dongfeng
D
Fujiwara
Kyoko
K
Igarashi
Jun
J
Makuuchi
Masatoshi
M
Hui
Ai-Min
AM
Tsurumaru
Masahiko
M
Nagase
Hiroki
H
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism; D019295:Computational Biology; D018899:CpG Islands; D003433:Crosses, Genetic; D019175:DNA Methylation; D017931:DNA Primers / Q000737:chemistry; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009077:Mucins / Q000096:biosynthesis* / Q000235:genetics*; D009124:Muscle Proteins / Q000096:biosynthesis* / Q000235:genetics*; D010455:Peptides / Q000737:chemistry; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013447:Sulfites / Q000494:pharmacology; D000071165:Trefoil Factor-3
D017931:DNA Primers; D009077:Mucins; D009124:Muscle Proteins; D010455:Peptides; D012333:RNA, Messenger; D013447:Sulfites; C082495:TFF3 protein, human; D000071165:Trefoil Factor-3