Expression analysis of pancreatic cancer cell lines reveals association of enhanced gene transcription and genomic amplifications at the 8q22.1 and 8q24.22 loci.
Despite tremendous effort and progress in the diagnostics of pancreatic cancer with respect to imaging techniques and molecular genetics, only very few patients can be cured by surgery leading to a 5-year survival rate of only 3%. Especially the lack of chemotherapeutical options in this entity requires a better understanding of the molecular mechanisms leading to pancreatic carcinoma growth and progression in order to develop novel treatment regimens. To identify signaling pathways that are critical for this tumor entity, we compared six well-established pancreatic cancer cell lines (Capan-1, Capan-2, HUP-T3, HUP-T4, KCL-MOH, PaTu-8903) with colon cancer cell lines and tumor cell lines of non-epithelial origin by expression profiling. For this purpose we employed Human Genome Focus Arrays representing about 8500 well annotated human genes. We identified 353 genes with significantly high expression in the group of pancreatic carcinomas. Based on Gene Ontology annotations these genes are especially involved in Rho protein signal transduction, proteasome activator activity, cell motility, apoptotic program, and cell-cell adhesion processes indicating these pathways to be interesting candidates for the design of targeted therapies. Most pancreatic carcinomas are characterized by mutations in the TP53 and the KRAS genes and the absence of microsatellite instability, which could also be confirmed for our panel of pancreatic carcinoma cell lines. Looking for individual differences within this group that may be responsible for more or less aggressive behavior, we identified genomic amplifications at the 8q22.1 and the 8q24.22 loci to be associated with enhanced gene transcription. Because we have previously shown that gains of genomic material from the long arm of chromosome 8 have an adverse effect on the outcome of pancreatic carcinoma patients, we conclude that functional analysis of amplified genes at 8q22 and/or 8q24 may lead to an improved understanding of pancreatic carcinoma progression.
Domagk
Dirk
D
Department of Medicine B, Interdisciplinary Center for Clinical Research, University of Muenster, Muenster, Germany, and Childrens Hospital of Los Angeles, CA, USA.
Schaefer
Karl-Ludwig
KL
Eisenacher
Martin
M
Braun
Yvonne
Y
Wai
Daniel H
DH
Schleicher
Christina
C
Diallo-Danebrock
Raihanatou
R
Bojar
Hans
H
Roeder
Gernot
G
Gabbert
Helmut E
HE
Domschke
Wolfram
W
Poremba
Christopher
C
D017209:Apoptosis; D045744:Cell Line, Tumor; D002874:Chromosome Mapping; D002898:Chromosomes, Human, Pair 8; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D011905:Genes, ras; D015894:Genome, Human; D006801:Humans; D018895:Microsatellite Repeats; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D014158:Transcription, Genetic