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. 2003 Apr;162(4):1151-62.
doi: 10.1016/S0002-9440(10)63911-9.

Exploration of global gene expression patterns in pancreatic adenocarcinoma using cDNA microarrays

Christine A Iacobuzio-Donahue  1 , Anirban Maitra, Mari Olsen, Anson W Lowe, N Tjarda van Heek, Christophe Rosty, Kim Walter, Norihiro Sato, Antony Parker, Raheela Ashfaq, Elizabeth Jaffee, Byungwoo Ryu, Jessa Jones, James R Eshleman, Charles J Yeo, John L Cameron, Scott E Kern, Ralph H Hruban, Patrick O Brown, Michael Goggins
Affiliations

Exploration of global gene expression patterns in pancreatic adenocarcinoma using cDNA microarrays

Christine A Iacobuzio-Donahue et al. Am J Pathol. 2003 Apr.

Abstract

Pancreatic cancer is the fifth leading cause of cancer death in the United States. We used cDNA microarrays to analyze global gene expression patterns in 14 pancreatic cancer cell lines, 17 resected infiltrating pancreatic cancer tissues, and 5 samples of normal pancreas to identify genes that are differentially expressed in pancreatic cancer. We found more than 400 cDNAs corresponding to genes that were differentially expressed in the pancreatic cancer tissues and cell lines as compared to normal pancreas. These genes that tended to be expressed at higher levels in pancreatic cancers were associated with a variety of processes, including cell-cell and cell-matrix interactions, cytoskeletal remodeling, proteolytic activity, and Ca(++) homeostasis. Two prominent clusters of genes were related to the high rates of cellular proliferation in pancreatic cancer cell lines and the host desmoplastic response in the resected pancreatic cancer tissues. Of 149 genes identified as more highly expressed in the pancreatic cancers compared with normal pancreas, 103 genes have not been previously reported in association with pancreatic cancer. The expression patterns of 14 of these highly expressed genes were validated by either immunohistochemistry or reverse transcriptase-polymerase chain reaction as being expressed in pancreatic cancer. The overexpression of one gene in particular, 14-3-3 sigma, was found to be associated with aberrant hypomethylation in the majority of pancreatic cancers analyzed. The genes and expressed sequence tags presented in this study provide clues to the pathobiology of pancreatic cancer and implicate a large number of potentially new molecular markers for the detection and treatment of pancreatic cancer.

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Figures

Figure 1.
Figure 1.
Profiles of gene expression in pancreatic samples. A: Dendrogram representing the results of hierarchical cluster analysis of the gene expression patterns in 36 pancreatic samples, based on data for 1492 genes. Sample names highlighted in green are normal pancreatic tissue (n = 5), samples in red are pancreatic primary tumor tissues (n = 17), and samples listed in black are pancreatic cancer cell lines (n = 14). B: Hierarchical cluster analysis of 1492 genes whose expression varied by at least two standard deviations from the mean in at least two samples. Five clusters of gene expression with similar patterns of variation in expression are highlighted, corresponding to acinar or islet gene expression in normal pancreas (white vertical bar), desmoplasia-associated gene expression (dark gray vertical bar), cell line-specific expression (black vertical bar), and genes differentially expressed in pancreas cancers (light gray vertical bars). The ratio of the abundance of transcripts of each gene in a given sample to its median abundance across all cell lines or tissue samples is represented by the color of the corresponding cell in the Tree View-generated diagram. Green cells are those with transcript levels below the median, black cells are equal to the median, and red cells are greater than the median. Gray cells represent technically inadequate or missing data. Color saturation of each cell reflects the magnitude of the ratio relative to the mean for each gene. The complete dataset is freely available at http://genome-www.stanford.edu/pancreatic1.
Figure 2.
Figure 2.
Immunohistochemical validation of selected highly expressed gene products detected by SAM. Shown are 14-3-3ς (A and B), transglutaminase II (C and D), cdc2 (E and F), and fibronectin (G and H). Strong positive immunohistochemical labeling of 14-3-3ς, transglutaminase II, and cdc2 proteins are detected in the neoplastic epithelium of infiltrating pancreatic ductal adenocarcinomas, but not in normal duct epithelium within the same tissue sections. In contrast, fibronectin is expressed predominantly by the host stromal response. Original magnifications, ×400.
Figure 3.
Figure 3.
RT-PCR validation of highly expressed genes identified by SAM. Shown are 20 pancreatic cancer cell lines, an immortal human pancreatic ductal epithelial cell line (HPDE6), and a water control. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) serves as an RNA control. Claudin 4 is expressed in 19 of 20 pancreatic cancer cell lines.
Figure 4.
Figure 4.
Methylation of 14-3-3ς promoter region in pancreatic cancer cell lines. A: DNA extracted from normal pancreatic epithelium (NP) and pancreatic cancer cell lines were amplified with primers specific to the unmethylated (U) or the methylated (M) templates after modification with sodium bisulfite. All normal pancreas samples permitted amplification of both methylated and unmethylated alleles, in contrast to 17 of 20 (85%) pancreatic cancer cell lines in which there was amplification of only unmethylated templates. One cell line, MiaPaCa2, shows complete methylation at 14-3-3ς. B: 14-3-3ς mRNA expression is detected in 19 cell lines with at least one unmethylated 14-3-3ς allele. Treatment of MiaPaCa2 cells with 5-aza-dC resulted in re-expression of 14-3-3ς.
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