Beta-catenin--a linchpin in colorectal carcinogenesis?
An important role for beta-catenin pathways in colorectal carcinogenesis was first suggested by the protein's association with adenomatous polyposis coli (APC) protein, and by evidence of dysregulation of beta-catenin protein expression at all stages of the adenoma-carcinoma sequence. Recent studies have, however, shown that yet more components of colorectal carcinogenesis are linked to beta-catenin pathways. Pro-oncogenic factors that also release beta-catenin from the adherens complex and/or encourage translocation to the nucleus include ras, epidermal growth factor (EGF), c-erbB-2, PKC-betaII, MUC1, and PPAR-gamma, whereas anti-oncogenic factors that also inhibit nuclear beta-catenin signaling include transforming growth factor (TGF)-beta, retinoic acid, and vitamin D. Association of nuclear beta-catenin with the T cell factor (TCF)/lymphoid enhancer factor (LEF) family of transcription factors promotes the expression of several compounds that have important roles in the development and progression of colorectal carcinoma, namely: c-myc, cyclin D1, gastrin, cyclooxygenase (COX)-2, matrix metalloproteinase (MMP)-7, urokinase-type plasminogen activator receptor (aPAR), CD44 proteins, and P-glycoprotein. Finally, genetic aberrations of several components of the beta-catenin pathways, eg, Frizzled (Frz), AXIN, and TCF-4, may potentially contribute to colorectal carcinogenesis. In discussing the above interactions, this review demonstrates that beta-catenin represents a key molecule in the development of colorectal carcinoma.
Wong
Newton Alexander Chiang Shuek
NA
Department of Pathology, University of Edinburgh, Edinburgh, Scotland, United Kingdom.
Pignatelli
Massimo
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000236:Adenoma / Q000473:pathology / Q000503:physiopathology*; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002277:Carcinoma / Q000473:pathology / Q000503:physiopathology*; D015179:Colorectal Neoplasms / Q000473:pathology / Q000503:physiopathology*; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D005755:Gastrins / Q000235:genetics / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism; D007413:Intestinal Mucosa / Q000166:cytology; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D020783:Matrix Metalloproteinase 7 / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators; D051176:beta Catenin
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D025601:Adenomatous Polyposis Coli Protein; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D005755:Gastrins; D018960:Hyaluronan Receptors; D007527:Isoenzymes; D008565:Membrane Proteins; C524898:PLAUR protein, human; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D015534:Trans-Activators; D051176:beta Catenin; D019938:Cyclin D1; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3; D020783:Matrix Metalloproteinase 7