Wingless-type frizzled protein receptor signaling and its putative role in human colon cancer.
We wish to identify new candidate genes involved in the pathogenesis of human colon cancer to better understand the diversity of phenotype presentation that varies from individual to individual. Our working hypothesis is that genetic polymorphism of genes in the Wingless-type (Wnt) frizzled protein receptor pathway is associated with the susceptibility to develop colon cancer. The putative role of the Wnt pathway in sporadic human malignancy of the colon suggests involvement in inherited cancer as well. beta-catenin is the crucial messenger in frizzled receptor signaling, transmitting Wnt-ligand signals such as signals from secreted apoptosis-related proteins to the nucleus. It functions as a genome denunciator by initiating amplification of oncogenes. The net effect of beta-catenin depends on the magnitude of its accumulation in the cytoplasm and, therefore, upon expression profiles of genes in the Wnt pathway. We propose that variations in allelic frequencies of genes involved in the beta-catenin cascade may either promote or impede malignant transformation of the colon. If certain polymorphisms in Wnt signaling through beta-catenin predispose to colon cancer, this might manifest as decreased binding affinity of proteins such as axin or the adenomatous polyposis coli protein to beta-catenin. Association studies are proposed to test the hypothesis, which could serve as an initial step toward understanding the complexity of tumor biology. The clinical rationale in unraveling the genetic susceptibility to cancer lies in identification of a subgroup of individuals who may benefit from beta-catenin targeting agents, which could potentially overcome this genetic instability.
Uthoff
S M
SM
Digestive Surgery Research Laboratory, Department of Surgery, University of Louisville School of Medicine, Louisville, Kentucky, USA.
Eichenberger
M R
MR
McAuliffe
T L
TL
Hamilton
C J
CJ
Galandiuk
S
S
D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000502:physiology*; D051157:Frizzled Receptors; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D010750:Phosphoproteins / Q000502:physiology; D011494:Protein Kinases / Q000502:physiology; D011506:Proteins / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000235:genetics*; D015398:Signal Transduction; D051153:Wnt Proteins; D029961:Zebrafish Proteins
D003598:Cytoskeletal Proteins; D051157:Frizzled Receptors; D010750:Phosphoproteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D011494:Protein Kinases