Researchers led by Dr. Dalila Darmoul of the Institut National de la Santι et de la Recherche Mιdicale (INSERM) in Paris, France have found that Kallikrein-related peptidase 4 (KLK4) may activated protease-activated receptors (PARs), promoting the development of colon cancer.
They report their data in the March 2010 issue of The American Journal of Pathology.
Colon cancer causes 655,000 deaths worldwide per year and is the fifth most common form of cancer in the United States. Colon cancers arise from usually benign polyps in the colon, which may develop into cancer over time.
Proteases promote cancer progression both by degrading the extracellular matrix and by signaling through PARs, which can induce proliferation and motility in colon cancer cells. The physiological activators of PARs in colon cancer remain unknown. Gratio et al hypothesized that KLKs, which have been shown to function as PAR activators in vitro and in vivo, may activate PARs in colon cancer. They found that KLK-4 was expressed in colon adenocarcinomas, but absent from normal endothelium, and that KLK-4 expression resulted in loss of PAR1 and PAR2 in a colon cancer cell line. Taken together, these results suggest that KLK-4 may be an endogenous ligand for PAR activation in colon cancer and therefore may provide a novel therapeutic target.
Dr. Darmoul's group indicates that "concomitant upregulation of KLK4 and PAR1 in colonic tumors would suggest that KLK4-mediated PAR1 activation could play an important role in colon tumorigenesis."
- Gratio V, Beaufort N, Seiz L, Maier J, Virca GD, Debela M, Grebenchtchikov N, Magdolen V, Darmoul D. Kallikrein-related peptidase 4 (KLK4): a new activator of the aberrantly expressed protease-activated receptor 1 in colon cancer cells. Am J Pathol, 2010, 176 1452-1461
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