[beta-Catenin induces invasive growth by activating matrix metalloproteinases in colorectal carcinoma].
beta-catenin was shown to be a major oncoprotein in colon cancer development. Its oncogenic function as a transcriptional activator is upregulated by mutations in the APC tumor suppressor gene, leading to a constitutive activation of the proliferation-associated genes c-myc and cyclin D. The aim of this study was to demonstrate a role of APC-mutations and dysregulated beta-catenin also for the progression of colorectal cancer, by identifying new target genes of beta-catenin associated with tumor invasion and metastasis. Potential invasion genes regulated by beta-catenin and its DNA binding partner TCF4 were identified by a computer search for the consensus DNA binding sequence in relevant promoter regions. Specific DNA binding was confirmed by gel shift assays. Functional importance of beta-catenin for the activation of identified genes was determined by luciferase reporter assays. The significance was demonstrated by coexpression of nuclear beta-catenin and the identified target genes by immunohistochemistry. Among other invasion genes, we identified the matrix metallo proteinases MMP-7 and MMP-1 activated by beta-catenin in the tumor cells. MMP-7 is an important factor for invasion and metastasis and overexpressed in 75% of colon carcinomas. The significance for human colon cancer development was demonstrated by a correlated overexpression of beta-catenin and the MMPs, beginning in large, severely dysplastic adenomas. Our results explain the high percentage of MMP-7 overexpression in colorectal tumors and the resulting activation of invasive growth. Moreover by identifying dysregulated beta-catenin as a transcriptional activator of MMPs and other invasion factors, we demonstrated an important role of mutated APC not only for early steps but also for the progression of colorectal carcinogenesis.
Brabletz
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Pathologisches Institut, Universität Erlangen-Nürnberg, Germany.
Jung
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A
Dag
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Reu
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Kirchner
T
T
D015820:Cadherins / Q000502:physiology; D002455:Cell Division; D003110:Colonic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D003598:Cytoskeletal Proteins / Q000502:physiology*; D017491:Genes, APC; D006801:Humans; D020783:Matrix Metalloproteinase 7 / Q000235:genetics; D020782:Matrix Metalloproteinases / Q000235:genetics* / Q000378:metabolism; D009361:Neoplasm Invasiveness; D012189:Retrospective Studies; D015534:Trans-Activators; D014158:Transcription, Genetic; D051176:beta Catenin
C495270:CTNNB1 protein, human; D015820:Cadherins; D003598:Cytoskeletal Proteins; D015534:Trans-Activators; D051176:beta Catenin; D020782:Matrix Metalloproteinases; D020783:Matrix Metalloproteinase 7
beta-Catenin induziert invasives Wachstum durch die Aktivierung von Matrixmetalloproteinasen in kolorektalen Karzinomen.