Identification of consensus genes and key regulatory elements in 5-fluorouracil resistance in gastric and colon cancer.
BACKGROUND
5-fluorouracil (5-FU) is widely used in the treatment of gastric and colorectal cancer. Recent microrarray studies associated different gene lists with 5-FU resistance. A major challenge in the genomic era is to find the most validated genes, and to decipher the regulatory networks responsible for the expression changes in a set of co-regulated transcripts. Our aim was to find genes repeatedly associated with 5-FU resistance, and to identify transcription factors (TFs) having overrepresented binding sites (TFBSs) in the promoter regions of genes associated with 5-FU resistance.


METHODS
The analyzed data originated from 5 different publications describing genome-wide gene expression patterns associated with 5- FU resistance in gastric and colorectal cancer. First, a data warehouse containing all genes associated with resistance was set up. 39 genes were identified which were repeatedly associated with resistance. Of these, using the EZ-Retrieve web service, proximal promoter sequences were available for 33 genes. The MotifScanner software was used to detect TFBSs in this set of sequences.


RESULTS
A total of 200 different TFBSs were identified. Using the statistics tool of the Java program TOUCAN, 4 binding sites were found to be significantly overrepresented: NFKappaB50 (p = 0.01), EGR2 (p = 0.027), EGR3 (p = 0.007), and NGFIC (or EGR4) (p = 0.001). These genes intercept apoptotic pathways at multiple locations in the tumor cells.


CONCLUSIONS
We identified a consensus gene list associated with 5-FU resistance, performed an in silico comparative promoter analysis, and highlighted the potential implication of some TFs in the development of chemoresistance.
Szöke
Dominika
D
Semmelweis University Budapest, 1st Dept. of Pediatrics, Budapest, Hungary.
Györffy
András
A
Surowiak
Pawel
P
Tulassay
Zsolt
Z
Dietel
Manfred
M
Györffy
Balázs
B
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005472:Fluorouracil / Q000008:administration & dosage*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics*; D012189:Retrospective Studies; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics*
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; D005472:Fluorouracil