The molecular mechanisms underlying the genesis of cholangiocarcinomas (CCs) are poorly understood. Epigenetic changes such as aberrant hypermethylation and subsequent atypical gene expression are characteristic features of most human cancers. In CC, data regarding global methylation changes are lacking so far. We performed a genome-wide analysis for aberrant promoter methylation in human CCs. We profiled 10 intrahepatic and 8 extrahepatic CCs in comparison to non-neoplastic biliary tissue specimens, using methyl-CpG immunoprecipitation (MCIp) combined with whole-genome CpG island arrays. DNA methylation was confirmed by quantitative mass spectrometric analysis and functional relevance of promoter hypermethylation was shown in demethylation experiments of two CC cell lines using 5-aza-2'deoxycytidine (DAC) treatment. Immunohistochemical staining of tissue microarrays (TMAs) from 223 biliary tract cancers (BTCs) was used to analyze candidate gene expression at the protein level. Differentially methylated, promoter-associated regions were nonrandomly distributed and enriched for genes involved in cancer-related pathways including Wnt, transforming growth factor beta (TGF-β), and PI3K signaling pathways. In CC cell lines, silencing of genes involved in Wnt signaling, such as SOX17, WNT3A, DKK2, SFRP1, SFRP2, and SFRP4 was reversed after DAC administration. Candidate protein SFRP2 was substantially down-regulated in neoplastic tissues of all BTC subtypes as compared to normal tissues. A significant inverse correlation of SFRP2 protein expression and pT status was found in BTC patients.
Pharmacology, Toxicology and Pharmaceutical Science
2
3%
Arts and Humanities
1
1%
Other
2
3%
Unknown
22
29%
Attention Score in Context
Attention Score in Context
This research output has an Altmetric Attention Score of 3. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 04 January 2014.
All research outputs
#9,437,703
of 27,507,170 outputs
Outputs from Hepatology
#5,256
of 10,225 outputs
Outputs of similar age
#103,280
of 329,910 outputs
Outputs of similar age from Hepatology
#61
of 102 outputs
Altmetric has tracked 27,507,170 research outputs across all sources so far. This one is in the 42nd percentile – i.e., 42% of other outputs scored the same or lower than it.
So far Altmetric has tracked 10,225 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 11.7. This one is in the 25th percentile – i.e., 25% of its peers scored the same or lower than it.
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We're also able to compare this research output to 102 others from the same source and published within six weeks on either side of this one. This one is in the 35th percentile – i.e., 35% of its contemporaries scored the same or lower than it.
