Abstract
BackgroundIn a previous report we have demonstrated that the chymotryptic-like serine protease kallikrein 7 (KLK7/hK7) is overexpressed in pancreatic cancer. In normal skin, hK7 is thought to participate in skin desquamation by contributing in the degradation of desmosomal components, such as desmogleins. Thus, the ability of hK7 to degrade desmogleins was assessed and the effect of hK7 expression on desmoglein 2 was examined in cultured pancreatic cancer cells.MethodsThe expression of Dsg1, Dsg2, and Dsg3 in pancreatic tissues was examined by immunohistochemistry and their expression in two pancreatic cancer cell lines, BxPC-3 and Panc-1, was determined by western blot analysis. The ability of hK7 to degrade Dsg1 and Dsg2 was investigated using in vitro degradation assays. BxPC-3 cells stably transfected to overexpress hK7 were used to examine the effect of hK7 on cell-surface resident Dsg2.ResultsThe levels of immunoreactive Dsg1 and Dsg2 were reduced in pancreatic adenocarcinomas compared with both normal pancreatic and chronic pancreatitis tissues. Among the desmosomal proteins examined, Dsg2 exhibited robust expression on the surface of BxPC-3 cells. When hK7 was overexpressed in this cell line, there was a significant increase in the amount of soluble Dsg2 released into the culture medium compared with vector-transfected control cells.ConclusionA reduction in the amount of the cell adhesion components Dsg1 and Dsg2 in pancreatic tumors suggests that loss of these desmosomal proteins may play a role in pancreatic cancer invasion. Using in vitro degradation assays, both Dsg1 and Dsg2 could be readily proteolyzed by hK7, which is overexpressed in pancreatic adenocarcinomas. The enforced expression of hK7 in BxPC-3 cells that express significant amounts of Dsg2 resulted in a marked increase in the shedding of soluble Dsg2, which is consistent with the notion that aberrant expression of hK7 in pancreatic tumors may result in diminished cell-cell adhesion and facilitate tumor cell invasion.
Highlights
In a previous report we have demonstrated that the chymotryptic-like serine protease kallikrein 7 (KLK7/Human kallikrein 7 (hK7)) is overexpressed in pancreatic cancer
Intensity of membrane staining for desmosomal proteins Dsg1 and Dsg2 is lower in human pancreatic cancer compared to normal pancreas and chronic pancreatitis Six independent sections of normal human pancreas, chronic pancreatitis, or pancreatic adenocarcinoma tissue were stained for desmogleins 1, 2, and 3
In this report we have shown that the levels of cell-surface resident Dsg1 and Dsg2 are reduced in pancreatic adenocarcinomas compared with normal and chronic pancreatitis tissues
Summary
In a previous report we have demonstrated that the chymotryptic-like serine protease kallikrein 7 (KLK7/hK7) is overexpressed in pancreatic cancer. The ability of hK7 to degrade desmogleins was assessed and the effect of hK7 expression on desmoglein 2 was examined in cultured pancreatic cancer cells. Pancreatic cancer is highly invasive and is characterized by early metastasis. The core of the desmosomal adhesive complex primarily consists of desmogleins (Dsg) and desmocollins (Dsc), glycoproteins belonging to the cadherin superfamily of proteins. As seen with many other important adhesion molecules, alterations in the expression of various members of desmosomal family of proteins have been observed in different types of cancer [5]. There is, a lack of complete understanding regarding the expression of desmosomal proteins in many different types of cancer and the mechanism by which cancer cells may regulate and overcome the adhesion mediated by desmosomal proteins
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