Serine proteinases participate in
tumor growth and invasion by cleaving and activating
proteinase-activated receptors (PARs). Recent studies have implicated PAR-1 and PAR-4 (activated by
thrombin) and PAR-2 (activated by
trypsin but not by
thrombin) in human
colon cancer growth. The endogenous activators of PARs in colon
tumors, however, are still unknown. We hypothesize that the
kallikrein-related
peptidase (KLK) family member KLK14, a known
tumor biomarker, is produced by colonic
tumors and signals to human
colon cancer cells by activating PARs. We found that i) KLK14
mRNA was present in 16 human
colon cancer cell lines, ii) KLK14
protein was expressed and secreted in
colon cancer cell lines, and iii) KLK14 (0.1 μmol/L) induced increases in intracellular
calcium in HT29, a human
colon cancer-derived cell line. KLK14-induced
calcium flux was associated with internalization of KLK14-mediated activation of PAR-2. Furthermore, KLK14 induced significant
extracellular signal-regulated kinases 1 and 2 (ERK1/2) phosphorylation and HT29 cell proliferation, presumably by activating PAR-2. A PAR-2 cleavage and activation-blocking antibody dramatically reduced KLK14-induced ERK1/2 signaling. Finally, ectopic expression of KLK14 in human
colon adenocarcinomas and its absence in normal epithelia was demonstrated by IHC analysis. These results demonstrate, for the first time, the aberrant expression of KLK14 in
colon cancer and its involvement in
PAR-2 receptor signaling. Thus, KLK14 and its
receptor, PAR-2, may represent therapeutic targets for colon
tumorigenesis.