β‐Catenin activates a coordinated expression of the proinvasive factors laminin‐5 γ2 chain and MT1‐MMP in colorectal carcinomas

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Abstract
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 β-catenin, predominantly at the invasive front within the tumor host interface. Various identified genes activated by β-catenin are associated with tumor invasion. One prerequisite for malignant tumor invasion is the ability of tumor cells to migrate. We recently described the γ2 chain of laminin as another β-catenin target gene. Fragments of the laminin γ2 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 β-catenin, its target gene and MT1-MMP substrate laminin γ2 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 β-catenin/TCF through a TCF binding site in its promoter. These results suggest that nuclear β-catenin activates the coordinated expression of the interacting proinvasive proteins laminin γ2 chain and MT1-MMP, thereby leading to a promigratory activity at the invasive front of colorectal cancers. This further supports an important role of β-catenin for invasion and metastasis of colorectal carcinomas.