Abstract
Plakophilin3 (PKP3) loss results in increased transformation in multiple cell lines in vitro and increased tumor formation in vivo. A microarray analysis performed in the PKP3 knockdown clones, identified an inflammation associated gene signature in cell lines derived from stratified epithelia as opposed to cell lines derived from simple epithelia. However, in contrast to the inflammation associated gene signature, the expression of MMP7 was increased upon PKP3 knockdown in all the cell lines tested. Using vector driven RNA interference, it was demonstrated that MMP7 was required for in-vitro cell migration and invasion and tumor formation in vivo. The increase in MMP7 levels was due to the increase in levels of the Phosphatase of Regenerating Liver3 (PRL3), which is observed upon PKP3 loss. The results suggest that MMP7 over-expression may be one of the mechanisms by which PKP3 loss leads to increased cell invasion and tumor formation.
Highlights
Matrilysin (MMP7) is one of the smallest members of the MMP family and is a highly potent metallo-protease which can degrade casein, laminin, fibronectin, collagen III/IV/V/IX/X/XI, type I/II/IV/ V gelatins, elastin and proteoglycans [1, 2]
Our results suggest that in HCT116 cells, the increase in Matrix metalloprotease7 (MMP7) levels is driven by phosphatase of regenerating liver 3 (PRL-3) over-expression in the PKP3 knockdown clones and that MMP7 is required for tumor formation in-vivo upon PKP3 loss
The increase in MMP7 mRNA is dependent on the expression of PRL-3, whose levels are elevated upon PKP3 loss [30]
Summary
Matrilysin (MMP7) is one of the smallest members of the MMP family and is a highly potent metallo-protease which can degrade casein, laminin, fibronectin, collagen III/IV/V/IX/X/XI, type I/II/IV/ V gelatins, elastin and proteoglycans [1, 2]. MMP-7 is secreted by epithelial cells [3] and its over-expression has been observed in many tumor types such as colorectal cancer [4,5,6,7], epidermolysisbullosa associated skin cancer [8, 9], bladder cancer [10], gastric cancers [3, 11], pancreatic cancer [12] and esophageal cancer [13, 14]. Loss of MMP7 either by antisense RNA mediated knockdown in colorectal cancer cell lines or by knockout in mice leads to decreased tumor incidence, while an increase in MMP7 expression causes increased tumor formation [16,17,18]. Three major protein families contribute to desmosome assembly, the desmosomal cadherins
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