Beta-catenin activates a coordinated expression of the proinvasive factors laminin-5 gamma2 chain and MT1-MMP in colorectal carcinomas.
In colorectal carcinomas, loss-of-function mutations of the adenomatous polyposis coli (APC) tumor suppressor gene lead to a nuclear accumulation of the oncogenic transcriptional activator beta-catenin, predominantly at the invasive front within the tumor host interface. Various identified genes activated by beta-catenin are associated with tumor invasion. One prerequisite for malignant tumor invasion is the ability of tumor cells to migrate. We recently described the gamma2 chain of laminin as another beta-catenin target gene. Fragments of the laminin gamma2 chain, resulting from cleavage by the membrane type 1 matrix metalloproteinase (MT1-MMP), are strong inducers of epithelial cell migration. We here show a coordinated expression of nuclear beta-catenin, its target gene and MT1-MMP substrate laminin gamma2 chain, as well as MT1-MMP in tumor cells at invasive regions of colorectal carcinomas. We further demonstrate that MT1-MMP expression is regulated by beta-catenin/TCF through a TCF binding site in its promoter. These results suggest that nuclear beta-catenin activates the coordinated expression of the interacting proinvasive proteins laminin gamma2 chain and MT1-MMP, thereby leading to a promigratory activity at the invasive front of colorectal cancers. This further supports an important role of beta-catenin for invasion and metastasis of colorectal carcinomas.
Hlubek
Falk
F
Department of Pathology, University of Erlangen-Nürnberg, Erlangen, Germany. hlubek.falk@patho.imed.uni-erlangen.de
Spaderna
Simone
S
Jung
Andreas
A
Kirchner
Thomas
T
Brabletz
Thomas
T
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001665:Binding Sites; D015815:Cell Adhesion Molecules / Q000235:genetics* / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D003598:Cytoskeletal Proteins / Q000502:physiology*; D024202:Electrophoretic Mobility Shift Assay; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D007124:Immunoenzyme Techniques; D007797:Laminin / Q000235:genetics* / Q000378:metabolism; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000235:genetics* / Q000378:metabolism; D016612:Paraffin Embedding; D011401:Promoter Regions, Genetic; D015534:Trans-Activators / Q000502:physiology*; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D051176:beta Catenin; D000097794:Kalinin
D015815:Cell Adhesion Molecules; D003598:Cytoskeletal Proteins; D007797:Laminin; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D015534:Trans-Activators; D051176:beta Catenin; D000097794:Kalinin; C495270:CTNNB1 protein, human; C400567:LAMC2 protein, human