Frequent trefoil factor 3 (TFF3) overexpression and promoter hypomethylation in mouse and human hepatocellular carcinomas

Abstract

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.

Quantitative analysis of associations between DNA hypermethylation, hypomethylation, and DNMT RNA levels in ovarian tumors

“…Some cancer-linked global DNA hypomethylation can be attributed to a decrease in satellite DNA methylation, as we have demonstrated for breast cancers, Wilms tumors, and ovarian epithelial carcinomas (Narayan et al, 1998;Qu et al, 1999a;Jackson et al, 2004). Single-copy sequence hypomethylation in tumors is also observed (Feinberg and Vogelstein, 1983;Feinberg et al, 2002;Grunau et al, 2005;Okada et al, 2005). In numerous studies in which both DNA hypomethylation and local DNA hypermethylation (usually CpG islands in 5 0 gene or promoter regions) were investigated, these opposite epigenetic changes have been observed in the same tumors (Narayan et al, 1998;Santourlidis et al, 1999;Ehrlich et al, 2002).…”

Hypomethylated P4 Promoter Induces Expression of the Insulin-Like Growth Factor-II Gene in Hepatocellular Carcinoma in a Chinese Population

“…Several studies that have examined hypomethylation of promoter regions in various cancers have reported similar results. Okada et al (17) postulated that trefoil factor 3 promoter CpG hypomethylation may be one of the regulation mechanisms of trefoil factor 3 overexpression in HCC, and that it may be a critical process in mouse and human hepatocellular carcinogenesis. Xiao et al (41) found that MAGE-A1 mRNA expression in human hepatoma cell lines is associated with hypomethylation of the MAGE-A1 promoter domain.…”

Gene expression profile of DNA binding protein A transgenic mice

“…It is overexpressed in a wide range of human tumors of skin, breast, urogenital, gastrointestinal tract and liver (16)(17)(18)(19)(20)(21)(22)(23) and is thought to induce cancer cell growth. Tff3 overexpression appears to be a frequent event not only in spontaneous (23), transgenicinduced (23), chemically-induced (24) mouse liver tumors, but also in various risk factor-induced human HCC (23).…”