Global Alterations of DNA Methylation in Cholangiocarcinoma Target the Wnt Signaling Pathway

被引：115

作者：

Goeppert, Benjamin ^{[1
]}

Konermann, Carolin ^{[2
]}

Schmidt, Christopher Roman ^{[2
]}

Bogatyrova, Olga ^{[2
]}

Geiselhart, Lea ^{[2
]}

Ernst, Christina ^{[2
]}

Gu, Lei ^{[2
,6
]}

Becker, Natalia ^{[3
]}

Zucknick, Manuela ^{[3
]}

Mehrabi, Arianeb ^{[4
]}

Hafezi, Mohammadreza ^{[4
]}

Klauschen, Frederick ^{[5
]}

Stenzinger, Albrecht ^{[1
]}

Warth, Arne ^{[1
]}

Breuhahn, Kai ^{[1
]}

Renner, Marcus ^{[1
]}

Weichert, Wilko ^{[1
]}

Schirmacher, Peter ^{[1
]}

Plass, Christoph ^{[2
]}

Weichenhan, Dieter ^{[2
]}

机构：

[1] Univ Heidelberg Hosp, Inst Pathol, Heidelberg, Germany

[2] German Canc Res Ctr, Div Epigen & Canc Risk Factors, Heidelberg, Germany

[3] German Canc Res Ctr, Div Biostat, Heidelberg, Germany

[4] Univ Heidelberg Hosp, Dept Gen Visceral & Transplantat Surg, Heidelberg, Germany

[5] Charite, Inst Pathol, D-13353 Berlin, Germany

[6] German Canc Res Ctr, Div Theoret Bioinformat, Heidelberg, Germany

来源：

HEPATOLOGY | 2014年 / 59卷 / 02期

关键词：

PROMOTER METHYLATION; ALPHA-CATENIN; BETA-CATENIN; E-CADHERIN; GENE; EXPRESSION; BIOINFORMATICS; GENOME; FAMILY;

D O I：

10.1002/hep.26721

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

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-2deoxycytidine (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-), 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. Conclusion: We provide a comprehensive analysis to define the genome-wide methylation landscape of human CC. Several candidate genes of cancer-relevant signaling pathways were identified, and closer analysis of selected Wnt pathway genes confirmed the relevance of this pathway in CC. The presented global methylation data are the basis for future studies on epigenetic changes in cholangiocarcinogenesis. (Hepatology 2014;59:544-554)

引用

页码：544 / 554

页数：11

共 38 条

[1] The mode of tumour progression in combined hepatocellular carcinoma and cholangiocarcinoma: an immunohistochemical analysis of E-cadherin, alpha-catenin and beta-catenin [J].

Asayama, Y ;

Taguchi, K ;

Aishima, S ;

Nishi, H ;

Masuda, K ;

Tsuneyoshi, M .

LIVER, 2002, 22 (01) :43-50

[2] Expression of E-cadherin, α-catenin, β-catenin, and CD44 (Standard and variant isoforms) in human cholangiocarcinoma:: An immunohistochemical study [J].

Ashida, K ;

Terada, T ;

Kitamura, Y ;

Kaibara, N .

HEPATOLOGY, 1998, 27 (04) :974-982

[3] A decade of exploring the cancer epigenome - biological and translational implications [J].

Baylin, Stephen B. ;

Jones, Peter A. .

NATURE REVIEWS CANCER, 2011, 11 (10) :726-734

[4] Regional Activation of the Cancer Genome by Long-Range Epigenetic Remodeling [J].

Bert, Saul A. ;

Robinson, Mark D. ;

Strbenac, Dario ;

Statham, Aaron L. ;

Song, Jenny Z. ;

Hulf, Toby ;

Sutherland, Robert L. ;

Coolen, Marcel W. ;

Stirzaker, Clare ;

Clark, Susan J. .

CANCER CELL, 2013, 23 (01) :9-22

[5] Clinical diagnosis and staging of cholangiocarcinoma [J].

Blechacz, Boris ;

Komuta, Mina ;

Roskams, Tania ;

Gores, Gregory J. .

NATURE REVIEWS GASTROENTEROLOGY & HEPATOLOGY, 2011, 8 (09) :512-522

[6] Wnt/β-Catenin Signaling and Disease [J].

Clevers, Hans ;

Nusse, Roel .

CELL, 2012, 149 (06) :1192-1205

[7] Aberrant methylation of genes in low-grade astrocytomas. [J].

Costello J.F. ;

Plass C. ;

Cavenee W.K. .

Brain Tumor Pathology, 2000, 17 (2) :49-56

[8] Methylation matters [J].

Costello, JF ;

Plass, C .

JOURNAL OF MEDICAL GENETICS, 2001, 38 (05) :285-303

[9] Cholangiocarcinoma - Thirty-one-year experience with 564 patients at a single institution [J].

DeOliveira, Michelle L. ;

Cunningham, Steven C. ;

Cameron, John L. ;

Kamangar, Farin ;

Winter, Jordan M. ;

Lillemoe, Keith D. ;

Choti, Michael C. ;

Yeo, Charles J. ;

Schulick, Richard D. .

ANNALS OF SURGERY, 2007, 245 (05) :755-762

[10] Role of Nuclear Architecture in Epigenetic Alterations in Cancer [J].

Easwaran, H. P. ;

Baylin, S. B. .

NUCLEAR ORGANIZATION AND FUNCTION, 2010, 75 :507-515

← 1 2 3 4 →