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Identification of novel cellular targets in biliary tract cancers using global gene expression technology.

Publication ,  Journal Article
Hansel, DE; Rahman, A; Hidalgo, M; Thuluvath, PJ; Lillemoe, KD; Schulick, R; Ku, J-L; Park, J-G; Miyazaki, K; Ashfaq, R; Wistuba, II; Varma, R ...
Published in: Am J Pathol
July 2003

Biliary tract carcinoma carries a poor prognosis, and difficulties with clinical management in patients with advanced disease are often due to frequent late-stage diagnosis, lack of serum markers, and limited information regarding biliary tumor pathogenesis. RNA-based global analyses of gene expression have led to the identification of a large number of up-regulated genes in several cancer types. We have used the recently developed Affymetrix U133A gene expression microarrays containing nearly 22,000 unique transcripts to obtain global gene expression profiles from normal biliary epithelial scrapings (n = 5), surgically resected biliary carcinomas (n = 11), and biliary cancer cell lines (n = 9). Microarray hybridization data were normalized using dCHIP (http://www.dCHIP.org) to identify differentially up-regulated genes in primary biliary cancers and biliary cancer cell lines and their expression profiles was compared to that of normal epithelial scrapings using the dCHIP software as well as Significance Analysis of Microarrays or SAM (http://www-stat.stanford.edu/ approximately tibs/SAM/). Comparison of the dCHIP and SAM datasets revealed an overlapping list of 282 genes expressed at greater than threefold levels in the cancers compared to normal epithelium (t-test P <0.1 in dCHIP, and median false discovery rate <10 in SAM). Several pathways integral to tumorigenesis were up-regulated in the biliary cancers, including proliferation and cell cycle antigens (eg, cyclins D2 and E2, cdc2/p34, and geminin), transcription factors (eg, homeobox B7 and islet-1), growth factors and growth factor receptors (eg, hepatocyte growth factor, amphiregulin, and insulin-like growth factor 1 receptor), and enzymes modulating sensitivity to chemotherapeutic agents (eg, cystathionine beta synthase, dCMP deaminase, and CTP synthase). In addition, we identified several "pathway" genes that are rapidly emerging as novel therapeutic targets in cancer (eg, cytosolic phospholipase A2, an upstream target of the cyclooxygenase pathway, and ribosomal protein S6 kinase and eukaryotic translation initiation factor 4E, two important downstream mediators of the mitogenic Akt/mTOR signaling pathway). Overexpression of selected up-regulated genes was confirmed in tissue microarrays of biliary cancers by immunohistochemical analysis (n = 4) or in situ hybridization (n = 1), and in biliary cancer cell lines by reverse transcriptase PCR (n = 2). The majority of genes identified in the present study has not been previously reported in biliary cancers, and represent novel potential screening and therapeutic targets of this cancer type.

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Published In

Am J Pathol

DOI

ISSN

0002-9440

Publication Date

July 2003

Volume

163

Issue

1

Start / End Page

217 / 229

Location

United States

Related Subject Headings

  • Up-Regulation
  • Tumor Cells, Cultured
  • Phylogeny
  • Pathology
  • Oligonucleotide Array Sequence Analysis
  • In Situ Hybridization
  • Immunohistochemistry
  • Humans
  • Gene Expression Profiling
  • Carcinoma
 

Citation

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ICMJE
MLA
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Hansel, D. E., Rahman, A., Hidalgo, M., Thuluvath, P. J., Lillemoe, K. D., Schulick, R., … Maitra, A. (2003). Identification of novel cellular targets in biliary tract cancers using global gene expression technology. Am J Pathol, 163(1), 217–229. https://doi.org/10.1016/S0002-9440(10)63645-0
Hansel, Donna E., Ayman Rahman, Manuel Hidalgo, Paul J. Thuluvath, Keith D. Lillemoe, Richard Schulick, Ja-Lok Ku, et al. “Identification of novel cellular targets in biliary tract cancers using global gene expression technology.Am J Pathol 163, no. 1 (July 2003): 217–29. https://doi.org/10.1016/S0002-9440(10)63645-0.
Hansel DE, Rahman A, Hidalgo M, Thuluvath PJ, Lillemoe KD, Schulick R, et al. Identification of novel cellular targets in biliary tract cancers using global gene expression technology. Am J Pathol. 2003 Jul;163(1):217–29.
Hansel, Donna E., et al. “Identification of novel cellular targets in biliary tract cancers using global gene expression technology.Am J Pathol, vol. 163, no. 1, July 2003, pp. 217–29. Pubmed, doi:10.1016/S0002-9440(10)63645-0.
Hansel DE, Rahman A, Hidalgo M, Thuluvath PJ, Lillemoe KD, Schulick R, Ku J-L, Park J-G, 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 Jul;163(1):217–229.
Journal cover image

Published In

Am J Pathol

DOI

ISSN

0002-9440

Publication Date

July 2003

Volume

163

Issue

1

Start / End Page

217 / 229

Location

United States

Related Subject Headings

  • Up-Regulation
  • Tumor Cells, Cultured
  • Phylogeny
  • Pathology
  • Oligonucleotide Array Sequence Analysis
  • In Situ Hybridization
  • Immunohistochemistry
  • Humans
  • Gene Expression Profiling
  • Carcinoma