HDPR1, a novel inhibitor of the WNT/β-catenin signaling, is frequently downregulated in hepatocellular carcinoma: involvement of methylation-mediated gene silencing

Abstract

Oncogenic activation of the WNT/b-catenin signaling pathway is common in hepatocellular carcinoma (HCC). Dishevelled (Dvl), a key activator of the pathway, inhibits the adenomatous polyposis coli complex, and this leads to the accumulation of b-catenin and promotes tumorigenesis. Recently, a novel inhibitor of Dishevelled, namely Dapper (Dpr), was isolated in Xenopus. To explore whether HDPR1, the human homologue of Dpr, has an anti-oncogenic role in hepatocarcinogenesis, we studied the expression of this gene in HCCs. We found that there were two alternatively spliced transcripts of HDPR1, designated as a and b forms, in human liver. Downregulation of the gene expression was observed in 31 (43%) of the 72 human HCC samples using the primer pair that amplified both transcripts. Furthermore, the HDPR1a was downregulated in 42 (58%) of 72 human HCCs and the downregulation significantly correlated with accumulation of b-catenin. Also, downregulation of HDPR1 by RNA interference in HLE cells led to cytoplasmic accumulation of b-catenin. Furthermore, a CpG island located at the promoter region and exon 1 of the HDPR1 gene was methylated in 22 (51%) of human HCCs. We showed that downregulation of HDPR1, in hepatoma cell lines, was associated with methylation of this CpG island using bisulfite sequencing and 5-aza-2 0 -deoxycytidine demethylation experiment. In addition to methylation-mediated downregulation of HDPR1, allelic loss (13-28% of informative cases) was detected using microsatellite markers flanking the HDPR1 locus. To conclude, downregulation of HDPR1 is common in HCCs, frequently involves hypermethylation of the promoter region, and allelic loss of the HDPR1 locus may also play a role.

Functional interaction between Wnt3 and Frizzled-7 leads to activation of the Wnt/β-catenin signaling pathway in hepatocellular carcinoma cells

“…Previous reports suggest that several signaling components upstream of β-catenin may be involved for wild-type β-catenin accumulation to occur in HCC. These events include overexpression of FZD7 or Dishevelled, or down-regulation of the human homologue of Dapper 1 and SFRP1 by promoter hypermethylation [16,17,[39][40][41].…”

Relationships among MTHFR a1298c Gene Polymorphisms and Methylation Status of Dact1 Gene in Transitional Cell Carcinomas

“…Further-more, based on the evolutionary and functional conservation of Wnt signaling molecules, as well as the human chromosomal localization of DACT1, the DACT1gene is also predicted to be a potent cancerassociated gene (Katoh , 2003). DACT1 has been reported to be downregulated in hepatocellular carcinoma (Yau et al, 2005). A recent report identified a correlation between DACT1expression in lung cancer and poor histological grade, large tumor size, extent of tumor invasion, and lymph node metastasis (Yang et al, 2010).…”

Dysregulation of growth factor signaling in human hepatocellular carcinoma

“…Equally, FZD-7 is frequently overexpressed in HCCs (Merle et al, 2004). Dapper homolog 1 (HDPR1), an inhibitor of DSH, has been described to be downregulated in 58% of HCCs associated with the accumulation of b-catenin (Yau et al, 2005). Lastly, DKK-1 and -3, potential inhibitors of Wnt signaling, are dysregulated to a different extent in HCCs; however, the biological function of DKK in hepatocarcinogenesis is currently unclear (Wirths et al, 2003;Hsieh et al, 2004).…”