Oncogenic ras induces gastrin gene expression in colon cancer.
OBJECTIVE
The expression of gastrin, as a tumor growth factor, is significantly increased in some colon cancers compared with the low levels found in normal mucosa. The aim of this study was to elucidate the transcriptional mechanisms of gastrin induction in colon cancer.


METHODS
Gastrin messenger (mRNA) levels and K-ras genotype were determined in colon cancer cell lines and surgical specimens. Colon cancer cells were transfected with oncogenic ras expression vectors, and transcriptional activity was assayed with gastrin-luciferase reporter genes.


RESULTS
Colon cancer cell lines and tissues with K-ras mutations all had significantly higher gastrin mRNA levels than those that were ras wild type. Treatment of several ras mutant cell lines with PD98059, an inhibitor of mitogen-activated protein kinase kinase, resulted in a decrease in endogenous gastrin mRNA levels. The effects of ras on gastrin expression appeared to be mediated through the gastrin promoter because transfection of oncogenic ras and activated raf expression vectors both induced gastrin-promoter, luciferase-reporter genes. The inductive effects of oncogenic ras could be blocked by the coexpression of dominant negative forms of raf and extracellular regulated kinase.


CONCLUSIONS
Oncogenic ras induces gastrin gene expression through activation of the Raf-MEK-ERK signal transduction pathway.
Nakata
H
H
Division of Digestive Diseases and Nutrition, Department of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
Wang
S L
SL
Chung
D C
DC
Westwick
J K
JK
Tillotson
L G
LG
D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D003110:Colonic Neoplasms / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D005755:Gastrins / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D017930:Genes, Reporter / Q000235:genetics; D011905:Genes, ras / Q000502:physiology*; D005838:Genotype; D006801:Humans; D008156:Luciferases / Q000235:genetics; D020929:Mitogen-Activated Protein Kinase Kinases; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger / Q000378:metabolism
D004791:Enzyme Inhibitors; D005419:Flavonoids; D005755:Gastrins; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D008156:Luciferases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one