[beta-Catenin induces invasive growth by activating matrix metalloproteinases in colorectal carcinoma]

Verh Dtsch Ges Pathol. 2000;84:175-81.
[Article in German]

Abstract

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.

Publication types

  • English Abstract

MeSH terms

  • Cadherins / physiology
  • Cell Division
  • Colonic Neoplasms / enzymology
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / pathology*
  • Colorectal Neoplasms / enzymology
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / pathology*
  • Cytoskeletal Proteins / physiology*
  • Genes, APC
  • Humans
  • Matrix Metalloproteinase 7 / genetics
  • Matrix Metalloproteinases / genetics*
  • Matrix Metalloproteinases / metabolism
  • Neoplasm Invasiveness
  • Retrospective Studies
  • Trans-Activators*
  • Transcription, Genetic
  • beta Catenin

Substances

  • CTNNB1 protein, human
  • Cadherins
  • Cytoskeletal Proteins
  • Trans-Activators
  • beta Catenin
  • Matrix Metalloproteinases
  • Matrix Metalloproteinase 7