Kallikrein 7 enhances pancreatic cancer cell invasion by shedding E‐cadherin

BACKGROUND. Pancreatic cancer (PaC) is characterized by local invasion and early metastasis. Serine proteases have been associated with invasion and metastasis of many cancers due to their ability to degrade extracellular matrix (ECM) proteins and to activate other proteases; thus, the serine protea...

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Published in:Cancer 2007-05, Vol.109 (9), p.1811-1820
Main Authors: Johnson, Sarah K., Ramani, Vishnu C., Hennings, Leah, Haun, Randy S.
Format: Article
Language:English
Subjects:
Adenocarcinoma - metabolism
Adenocarcinoma - pathology
Biological and medical sciences
Cadherins - metabolism
cell aggregation
Cell Line, Tumor
Gastroenterology. Liver. Pancreas. Abdomen
Gene Expression
Gene Expression Profiling
Humans
Immunohistochemistry
Kallikreins - metabolism
Liver. Biliary tract. Portal circulation. Exocrine pancreas
Medical sciences
metastasis
Neoplasm Invasiveness
pancreatic cancer
Pancreatic Neoplasms - metabolism
Pancreatic Neoplasms - pathology
Reverse Transcriptase Polymerase Chain Reaction
serine proteinases
Tumors
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Summary:BACKGROUND. Pancreatic cancer (PaC) is characterized by local invasion and early metastasis. Serine proteases have been associated with invasion and metastasis of many cancers due to their ability to degrade extracellular matrix (ECM) proteins and to activate other proteases; thus, the serine proteases expressed in PaC were investigated. METHODS. An expression profile of serine proteases was generated from both normal and malignant pancreatic tissues using a polymerase chain reaction (PCR)‐based screen and differential expression of kallikrein 7 was examined by reverse‐transcriptase PCR (RT‐PCR) and immunohistochemical analyses. The ability of human kallikrein 7 (hK7) to cleave the epithelial cell adhesion molecule E‐cadherin was tested in vitro using both recombinant E‐cadherin and BxPC‐3 cells and the effects of hK7 proteolytic activity on pancreatic cell invasion and aggregation were examined. RESULTS. Expression profiling revealed that kallikrein 7 (KLK7) was overexpressed in pancreatic adenocarcinomas and its differential expression was confirmed by RT‐PCR analysis. hK7 was observed in neoplastic cells of all tumors examined with moderate‐to‐intense staining in 70% of tumors examined (16/23). In contrast, only 15% of nonmalignant tissue specimens (2/13) displayed moderate hK7 staining, whereas the remaining specimens yielded weak, if any, immunoreactivity. Using in vitro assays, hK7 was shown to cleave E‐cadherin and the soluble E‐cadherin fragment produced significantly enhanced Panc‐1 cell invasion through ECM proteins with a corresponding reduction in Panc‐1 cell aggregation. CONCLUSIONS. These results suggest that aberrant expression of KLK7 plays an important role in PaC and provides novel insight into the effects of elevated hK7 proteinase activity in this, and perhaps other, adenocarcinomas. Cancer 2007. © 2007 American Cancer Society. Kallikrein 7 is overexpressed in pancreatic tumors. Shedding of E‐cadherin by human kallikrein 7 (hK7) proteolytic activity increases pancreatic cell invasiveness and decreases cell aggregation.
ISSN:0008-543X
1097-0142
DOI:10.1002/cncr.22606