Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2011

Open Access 01-12-2011 | Research article

Genome-wide expression patterns associated with oncogenesis and sarcomatous transdifferentation of cholangiocarcinoma

Authors: Min-A Seol, In-Sun Chu, Mi-Jin Lee, Goung-Ran Yu, Xiang-Dan Cui, Baik-Hwan Cho, Eun-Kyung Ahn, Sun-Hee Leem, In-Hee Kim, Dae-Ghon Kim

Published in: BMC Cancer | Issue 1/2011

Login to get access

Abstract

Background

The molecular mechanisms of CC (cholangiocarcinoma) oncogenesis and progression are poorly understood. This study aimed to determine the genome-wide expression of genes related to CC oncogenesis and sarcomatous transdifferentiation.

Methods

Genes that were differentially expressed between CC cell lines or tissues and cultured normal biliary epithelial (NBE) cells were identified using DNA microarray technology. Expressions were validated in human CC tissues and cells.

Results

Using unsupervised hierarchical clustering analysis of the cell line and tissue samples, we identified a set of 342 commonly regulated (>2-fold change) genes. Of these, 53, including tumor-related genes, were upregulated, and 289, including tumor suppressor genes, were downregulated (<0.5 fold change). Expression of SPP1, EFNB2, E2F2, IRX3, PTTG1, PPARγ, KRT17, UCHL1, IGFBP7 and SPARC proteins was immunohistochemically verified in human and hamster CC tissues. Additional unsupervised hierarchical clustering analysis of sarcomatoid CC cells compared to three adenocarcinomatous CC cell lines revealed 292 differentially upregulated genes (>4-fold change), and 267 differentially downregulated genes (<0.25 fold change). The expression of 12 proteins was validated in the CC cell lines by immunoblot analysis and immunohistochemical staining. Of the proteins analyzed, we found upregulation of the expression of the epithelial-mesenchymal transition (EMT)-related proteins VIM and TWIST1, and restoration of the methylation-silenced proteins LDHB, BNIP3, UCHL1, and NPTX2 during sarcomatoid transdifferentiation of CC.

Conclusion

The deregulation of oncogenes, tumor suppressor genes, and methylation-related genes may be useful in identifying molecular targets for CC diagnosis and prognosis.
Appendix
Available only for authorised users
Literature
1.
Shaib YH, Davila JA, McGlynn K, El-Serag HB: Rising incidence of intrahepatic cholangiocarcinoma in the United States: a true increase?. J Hepatol. 2004, 40: 472-477. 10.1016/j.jhep.2003.11.030.CrossRefPubMed
2.
Blendis L, Halpern Z: An increasing incidence of cholangiocarcinoma: why?. Gastroenterology. 2004, 127: 1008-1009. 10.1053/j.gastro.2004.07.035.CrossRefPubMed
3.
Mittal B, Deutsch M, Iwatsuki S: Primary cancers of extrahepatic biliary passages. Int J Radiat Oncol Biol Phys. 1985, 11: 849-854. 10.1016/0360-3016(85)90320-7.CrossRefPubMed
4.
Pitt HA, Nakeeb A, Abrams RA, Coleman J, Piantadosi S, Yeo CJ, Lillemore KD, Cameron JL: Perihilar cholangiocarcinoma. Postoperative radiotherapy does not improve survival. Ann Surg. 1995, 221: 788-797. 10.1097/00000658-199506000-00017.CrossRefPubMedPubMedCentral
5.
Vauthey JN, Blumgart LH: Recent advances in the management of cholangiocarcinomas. Semin Liver Dis. 1994, 14: 109-114. 10.1055/s-2007-1007302.CrossRefPubMed
6.
Gores GJ: Cholangiocarcinoma: current concepts and insights. Hepatology. 2003, 37: 961-969. 10.1053/jhep.2003.50200.CrossRefPubMed
7.
Ohashi K, Nakajima Y, Kanehiro H, Tsutsumi M, Taki J, Aomatsu Y, Yoshimura A, Ko S, Kin T, Yagura K, Konishi Y, Nakano H: Ki-ras mutations and p53 protein expressions in intrahepatic cholangiocarcinomas: relation to gross tumor morphology. Gastroenterology. 1995, 109: 1612-1617. 10.1016/0016-5085(95)90650-9.CrossRefPubMed
8.
Furubo S, Harada K, Shimonishi T, Katayanagi K, Tsui W, Nakanuma Y: Protein expression and genetic alterations of p53 and ras in intrahepatic cholangiocarcinoma. Histopathology. 1999, 35: 230-240. 10.1046/j.1365-2559.1999.00705.x.CrossRefPubMed
9.
Tannapfel A, Sommerer F, Benicke M, Katalinic A, Uhlmann D, Witzigmann H, Hauss J, Wittekind C: Mutations of the BRAF gene in cholangiocarcinoma but not in hepatocellular carcinoma. Gut. 2003, 52: 706-712. 10.1136/gut.52.5.706.CrossRefPubMedPubMedCentral
10.
Endo K, Yoon BI, Pairojkul C, Demetris AJ, Sirica AE: ERBB-2 overexpression and cyclooxygenase-2 up-regulation in human cholangiocarcinoma and risk conditions. Hepatology. 2002, 36: 439-450. 10.1053/jhep.2002.34435.CrossRefPubMed
11.
Sugawara H, Yasoshima M, Katayanagi K, Kono N, Watanabe Y, Harada K, Nakanuma Y: Relationship between interleukin-6 and proliferation and differentiation in cholangiocarcinoma. Histopathology. 1998, 33: 145-153. 10.1046/j.1365-2559.1998.00445.x.CrossRefPubMed
12.
Xu X, Kobayashi S, Qiao W, Li C, Xiao C, Radaeva S, Stiles B, Wang RH, Ohara N, Yoshino T, LeRoith D, Torbenson MS, Gores GJ, Wu H, Gao B, Deng CX: Induction of intrahepatic cholangiocellular carcinoma by liver-specific disruption of Smad4 and Pten in mice. J Clin Invest. 2006, 116: 1843-1852. 10.1172/JCI27282.CrossRefPubMedPubMedCentral
13.
Nakajima T, Tajima Y, Sugano I, Nagao K, Kondo Y, Wada K: Intrahepatic cholangiocarcinoma with sarcomatous change. Clinicopathologic and immunohistochemical evaluation of seven cases. Cancer. 1993, 72: 1872-1877. 10.1002/1097-0142(19930915)72:6<1872::AID-CNCR2820720614>3.0.CO;2-N.CrossRefPubMed
14.
Aishima S, Kuroda Y, Asayama Y, Taguchi K, Nishihara Y, Taketomi A, Tsuneyoshi M: Prognostic impact of cholangiocellular and sarcomatous components in combined hepatocellular and cholangiocarcinoma. Hum Pathol. 2006, 37: 283-291. 10.1016/j.humpath.2005.08.019.CrossRefPubMed
15.
Hansel DE, Rahman A, Hidalgo M, Thuluvath PJ, Lillemoe KD, Shulick R, Ku JL, Park JG, Miyazaki K, Ashfaq R, Wistuba II, Varma R, Hawthorne L, Geradts J, Argani P, Maitra A: Identification of novel cellular targets in biliary tract cancers using global gene expression technology. Am J Pathol. 2003, 163: 217-229. 10.1016/S0002-9440(10)63645-0.CrossRefPubMedPubMedCentral
16.
Obama K, Ura K, Li M, Katagiri T, Tsunoda T, Nomura A, Satoh S, Nakamura Y, Furukawa Y: Genome-wide analysis of gene expression in human intrahepatic cholangiocarcinoma. Hepatology. 2005, 41: 1339-1348. 10.1002/hep.20718.CrossRefPubMed
17.
Kim DG, Park SY, You KR, Lee GB, Kim H, Moon WS, Chun YH, Park SH: Establishment and characterization of chromosomal aberrations in human cholangiocarcinoma cell lines by cross-species color banding. Genes Chromosomes Cancer. 2001, 30: 48-56. 10.1002/1098-2264(2000)9999:9999<::AID-GCC1053>3.0.CO;2-P.CrossRefPubMed
18.
Makuuchi M, Belghiti J, Belli G, Fan ST, Lau JW, Ringe B, Strasberg SM, Vauthey JN, Yamaoka Y, Yamasaki S, Working Group of the International Scientific Committee of the International Hepato-Pancreato-Biliary Association: IHPBA concordant classification of primary liver cancer: working group report. J Hepatobiliary Pancreat Surg. 2003, 10: 26-30.PubMed
19.
Lee MJ, Yu GR, Park SH, Cho BH, Ahn JS, Park HJ, Song EY, Kim DG: Identification of cystatin B as a potential serum marker in hepatocellular carcinoma. Clin Cancer Res. 2008, 14: 1080-1089. 10.1158/1078-0432.CCR-07-1615.CrossRefPubMed
20.
Yoon BI, Kim DY, Jang JJ, Han JH: Altered expression of thioredoxin reductase-1 in dysplastic bile ducts and cholangiocarcinoma in a hamster model. J Vet Sci. 2006, 7: 211-216.CrossRefPubMedPubMedCentral
21.
Gao Y, Kitagawa K, Hiramatsu Y, Kikuchi H, Isobe T, Shimada M, Uchida C, Hattori T, Oda T, Nakayama K, Nakayama KI, Tanaka T, Konno H, Kitagawa M: Up-regulation of GPR48 induced by down-regulation of p27Kip1 enhances carcinoma cell invasiveness and metastasis. Cancer Res. 2006, 66: 11623-11631. 10.1158/0008-5472.CAN-06-2629.CrossRefPubMed
22.
Wang Z, Hao Y, Lowe AW: The Adenocarcinoma-associated antigen, AGR2, promotes tumor growth, cell migration, and cellular transformation. Cancer Res. 2008, 68: 492-497. 10.1158/0008-5472.CAN-07-2930.CrossRefPubMed
23.
Ge X, Jin Q, Zhang F, Yan T, Zhai Q: PCAF acetylates {beta}-catenin and improves its stability. Mol Biol Cell. 2009, 20: 419-427. 10.1091/mbc.E08-08-0792.CrossRefPubMedPubMedCentral
24.
Moparthi SB, Arbman G, Wallin A, Kayed H, Kleeff J, Zentgraf H, Sun XF: Expression of MAC30 protein is related to survival and biological variables in primary and metastatic colorectal cancers. Int J Oncol. 2007, 30: 91-95.PubMed
25.
Saitoh T, Katoh M: FRAT1 and FRAT2, clustered in human chromosome 10q24.1 region, are up-regulated in gastric cancer. Int J Oncol. 2001, 19: 311-315.PubMed
26.
Tachibana M, Tonomoto Y, Hyakudomi R, Hyakudomi M, Hattori S, Ueda S, Kinugasa S, Yoshimura H: Expression and prognostic significance of EFNB2 and EphB4 genes in patients with oesophageal squamous cell carcinoma. Dig Liver Dis. 2007, 39: 725-732. 10.1016/j.dld.2007.05.013.CrossRefPubMed
27.
Bidus MA, Risinger JI, Chandramouli GV, Dainty LA, Litzi TJ, Berchuck A, Barrett JC, Maxwell GL: Prediction of lymph node metastasis in patients with endometrioid endometrial cancer using expression microarray. Clin Cancer Res. 2006, 12: 83-88. 10.1158/1078-0432.CCR-05-0835.CrossRefPubMed
28.
Chen B, Athanasiou M, Gu Q, Blair DG: Drm/Gremlin transcriptionally activates p21(Cip1) via a novel mechanism and inhibits neoplastic transformation. Biochem Biophys Res Commun. 2002, 295: 1135-1141. 10.1016/S0006-291X(02)00828-8.CrossRefPubMed
29.
Abeysinghe HR, Cao Q, Xu J, Pollock S, Veyberman Y, Guckert NL, Wang N: HY1 expression is associated with tumor suppression of human ovarian cancer. Cancer Genet Cytogenet. 2003, 143: 125-132. 10.1016/S0165-4608(02)00855-5.CrossRefPubMed
30.
Gagliardi AD, Kuo EY, Raulic S, Wagner GF, DiMattia GE: Human stanniocalcin-2 exhibits potent growth-suppressive properties in transgenic mice independently of growth hormone and IGFs. Am J Physiol Endocrinol Metab. 2005, 288: E92-105. 10.1152/ajpendo.00268.2004.CrossRefPubMed
31.
Shetty S, Shetty P, Idell S, Velusamy T, Bhandary YP, Shetty RS: Regulation of plasminogen activator inhibitor-1 expression by tumor suppressor protein p53. J Biol Chem. 2008, 283: 19570-19580. 10.1074/jbc.M710268200.CrossRefPubMedPubMedCentral
32.
Esposito I, Kayed H, Keleg S, Giese T, Sage EH, Schirmacher P, Friess H, Kleeff J: Tumor-suppressor function of SPARC-like protein 1/Hevin in pancreatic cancer. Neoplasia. 2007, 9: 8-17. 10.1593/neo.06646.CrossRefPubMedPubMedCentral
33.
Yang Z, Chang YJ, Miyamoto H, Ni J, Niu Y, Chen Z, Yao JL, di Sant'Agnese PA, Chang C: Transgelin functions as a suppressor via inhibition of ARA54-enhanced androgen receptor transactivation and prostate cancer cell growth. Mol Endocrinol. 2007, 21: 343-358. 10.1210/me.2006-0104.CrossRefPubMed
34.
Yoo HJ, Yun BR, Kwon JH, Ahn HS, Seol MA, Lee MJ, Yu GR, Yu HC, Hong B, Choi K, Kim DG: Genetic and expression alterations in association with the sarcomatous change of cholangiocarcinoma cells. Exp Mol Med. 2009, 41: 102-115. 10.3858/emm.2009.41.2.013.CrossRefPubMedPubMedCentral
35.
Tedeschi FA, Zalazar FE: HOXA9 gene expression in the chronic myeloid leukemia progression. Leuk Res. 2006, 30: 1453-1456. 10.1016/j.leukres.2006.02.022.CrossRefPubMed
36.
Walsh MD, Young JP, Leggett BA, Williams SH, Jass JR, McGuckin MA: The MUC13 cell surface mucin is highly expressed by human colorectal carcinomas. Hum Pathol. 2007, 38: 883-892. 10.1016/j.humpath.2006.11.020.CrossRefPubMed
37.
Kong U, Koo J, Choi K, Park J, Chang H: The expression of GAGE gene can predict aggressive biologic behavior of intestinal type of stomach cancer. Hepatogastroenterology. 2004, 51: 1519-1523.PubMed
38.
Chen YT, Scanlan MJ, Venditti CA, Chua R, Theiler G, Stevenson BJ, Iseli C, Gure AO, Vasicek T, Strausberg RL, Jongeneel CV, Old LJ, Simpson AJ: Identification of cancer/testis-antigen genes by massively parallel signature sequencing. Proc Natl Acad Sci USA. 2005, 102: 7940-7945. 10.1073/pnas.0502583102.CrossRefPubMedPubMedCentral
39.
Leiblich A, Cross SS, Catto JW, Phillips JT, Leung HY, Hamdy FC, Rehman I: Lactate dehydrogenase-B is silenced by promoter hypermethylation in human prostate cancer. Oncogene. 2006, 25: 2953-2960. 10.1038/sj.onc.1209262.CrossRefPubMed
40.
Abe T, Toyota M, Suzuki H, Murai M, Akino K, Ueno M, Nojima M, Yawata A, Miyakawa H, Suga T, Ito H, Endo T, Tokino T, Hinoda Y, Imai K: Upregulation of 23BNIP3 by 5-aza-2'-deoxycytidine sensitizes pancreatic cancer cells to hypoxia-mediated cell death. J Gastroenterol. 2005, 40: 504-510. 10.1007/s00535-005-1576-1.CrossRefPubMed
41.
Yu J, Tao Q, Cheung KF, Jin H, Poon FF, Wang X, Cheng YY, Röcken C, Ebert MP, Chan AT, Sung JJ: Epigenetic identification of ubiquitin carboxyl-terminal hydrolase L1 as a functional tumor suppressor and biomarker for hepatocellular carcinoma and other digestive tumors. Hepatology. 2008, 48: 508-518. 10.1002/hep.22343.CrossRefPubMed
42.
Sato N, Fukushima N, Maitra A, Matsubayashi H, Yeo CJ, Cameron JL, Hruban RH, Goggins M: Discovery of novel targets for aberrant methylation in pancreatic carcinoma using high-throughput microarrays. Cancer Res. 2003, 63: 3735-3742.PubMed
43.
Harada N, Mizoi T, Kinouchi M, Hoshi K, Ishii S, Shiiba K, Sasaki I, Matsuno S: Introduction of antisense CD44S cDNA down-regulates expression of overall CD44 isoforms and inhibits tumor growth and metastasis in highly metastatic colon carcinoma cells. Int J Cancer. 2001, 91: 67-75. 10.1002/1097-0215(20010101)91:1<67::AID-IJC1011>3.0.CO;2-D.CrossRefPubMed
44.
Pan HW, Ou YH, Peng SY, Liu SH, Lai PL, Lee PH, Sheu JC, Chen CL, Hsu HC: Overexpression of osteopontin is associated with intrahepatic metastasis, early recurrence, and poorer prognosis of surgically resected hepatocellular carcinoma. Cancer. 2003, 98: 119-127. 10.1002/cncr.11487.CrossRefPubMed
45.
Hass HG, Nehls O, Jobst J, Frilling A, Vogel U, Kaiser S: Identification of osteopontin as the most consistently over-expressed gene in intrahepatic cholangiocarcinoma: Detection by oligonucleotide microarray and real-time PCR analysis. World J Gastroenterol. 2008, 14: 2501-2510. 10.3748/wjg.14.2501.CrossRefPubMedPubMedCentral
46.
Tachibana M, Tonomoto Y, Hyakudomi R, Hyakudomi M, Hattori S, Ueda S, Kinugasa S, Yoshimura H: Expression and prognostic significance of EFNB2 and EphB4 genes in patients with oesophageal squamous cell carcinoma. Dig Liver Dis. 2007, 39: 725-732. 10.1016/j.dld.2007.05.013.CrossRefPubMed
47.
Steube KG, Meyer C, Habig S, Uphoff CC, Drexler HG: Expression of receptor tyrosine kinase HTK (hepatoma transmembrane kinase) and HTK ligand by human leukemia-lymphoma cell lines. Leuk Lymphoma. 1999, 33: 371-376.CrossRefPubMed
48.
Takai N, Miyazaki T, Fujisawa K, Nasu K, Miyakawa I: Expression of receptor tyrosine kinase EphB4 and its ligand ephrin-B2 is associated with malignant potential in endometrial cancer. Oncol Rep. 2001, 8: 567-573.PubMed
49.
Ren B, Cam H, Takahashi Y, Volkert T, Terragni J, Young RA, Dynlacht BD: E2F integrates cell cycle progression with DNA repair, replication, and G(2)/M checkpoints. Genes Dev. 2002, 16: 245-256. 10.1101/gad.949802.CrossRefPubMedPubMedCentral
50.
Surawska H, Ma PC, Salgia R: The role of ephrins and Eph receptors in cancer. Cytokine Growth Factor Rev. 2004, 15: 419-4133. 10.1016/j.cytogfr.2004.09.002.CrossRefPubMed
51.
52.
Ordway JM, Bedell JA, Citek RW, Nunberg A, Garrido A, Kendall R, Stevens JR, Cao D, Doerge RW, Korshunova Y, Holemon H, McPherson JD, Lakey N, Leon J, Martienssen RA, Jeddeloh JA: Comprehensive DNA methylation profiling in a human cancer genome identifies novel epigenetic targets. Carcinogenesis. 2006, 27: 2409-2423. 10.1093/carcin/bgl161.CrossRefPubMed
53.
Cho-Rok J, Yoo J, Jang YJ, Kim S, Chu IS, Yeom YI, Choi JY, Im DS: Adenovirus-mediated transfer of siRNA against PTTG1 inhibits liver cancer cell growth in vitro and in vivo. Hepatology. 2006, 43: 1042-1052. 10.1002/hep.21137.CrossRefPubMed
54.
Issemann I, Green S: Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature. 1990, 347: 645-650. 10.1038/347645a0.CrossRefPubMed
55.
Schaefer KL, Wada K, Takahashi H, Matsuhashi N, Ohnishi S, Wolfe MM, Turner JR, Nakajima A, Borkan SC, Saubermann LJ: Peroxisome proliferator-activated receptor gamma inhibition prevents adhesion to the extracellular matrix and induces anoikis in hepatocellular carcinoma cells. Cancer Res. 2005, 65: 2251-2259. 10.1158/0008-5472.CAN-04-3037.CrossRefPubMed
56.
Kristiansen G, Jacob J, Buckendahl AC, Grützmann R, Alldinger I, Sipos B, Klöppel G, Bahra M, Langrehr JM, Neuhaus P, Dietel M, Pilarsky C: Peroxisome proliferator-activated receptor γ is highly expressed in pancreatic cancer and is associated with shorter overall survival times. Clinical Cancer Research. 2006, 12: 6444-6451. 10.1158/1078-0432.CCR-06-0834.CrossRefPubMed
57.
Dandachi N, Hauser-Kronberger C, Moré E, Wiesener B, Hacker GW, Dietze O, Wirl G: Co-expression of tenascin-C and vimentin in human breast cancer cells indicates phenotypic transdifferentiation during tumour progression: correlation with histopathological parameters, hormone receptors, and oncoproteins. J Pathol. 2001, 193: 181-189. 10.1002/1096-9896(2000)9999:9999<::AID-PATH752>3.0.CO;2-V.CrossRefPubMed
58.
Lee TK, Poon RT, Yuen AP, Ling MT, Kwok WK, Wang XH, Wong YC, Guan XY, Man K, Chau KL, Fan ST: Twist overexpression correlates with hepatocellular carcinoma metastasis through induction of epithelial-mesenchymal transition. Clin Cancer Res. 2006, 12: 5369-5376. 10.1158/1078-0432.CCR-05-2722.CrossRefPubMed
Metadata
Title
Genome-wide expression patterns associated with oncogenesis and sarcomatous transdifferentation of cholangiocarcinoma
Authors
Min-A Seol
In-Sun Chu
Mi-Jin Lee
Goung-Ran Yu
Xiang-Dan Cui
Baik-Hwan Cho
Eun-Kyung Ahn
Sun-Hee Leem
In-Hee Kim
Dae-Ghon Kim
Publication date
01-12-2011
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2011
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-11-78

Other articles of this Issue 1/2011

BMC Cancer 1/2011 Go to the issue

Research article

COX-2 gene expression in colon cancer tissue related to regulating factors and promoter methylation status

Research article

Apoptosis-related deregulation of proteolytic activities and high serum levels of circulating nucleosomes and DNA in blood correlate with breast cancer progression

Research article

The effect of breast cancer awareness month on internet search activity - a comparison with awareness campaigns for lung and prostate cancer

Research article

Diagnostic value of circulating tumor cell detection in bladder and urothelial cancer: systematic review and meta-analysis

Research article

Cytoplasmic p21 is a potential predictor for cisplatin sensitivity in ovarian cancer

Research article

Validation of prognostic scores for survival in cancer patients beyond first-line therapy
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits