BACKGROUND/OBJECTIVES: The objective of this study was to assess the role of a secreted serine protease, kallikrein-related peptidase 6 (KLK6), during colorectal tumorigenesis driven by a mutant tumor suppressor gene. A first analysis of KLK6 expression in the intestinal tract of -mutant multiple intestinal neoplasia () mice revealed up to four-fold induction of mRNA levels in adenomas relative to its level in the adjacent mucosa.
METHODS AND RESULTS: The presence of KLK6 protein in the adenomatous areas was confirmed by immunohistochemistry and optical coherence tomography/laser-induced fluorescence (OCT/LIF) imaging. To assess the contribution of the KLK6 expression on the -mutant intestinal and colon tumorigenesis, we engineered a mouse with floxed alleles of the gene () and crossed it with a mouse expressing the truncated APC protein under control of the intestinal tract-specific human transgene (;). We found that mice with disrupted gene expression (;) had a significantly smaller average size of the small intestinal and colon crypts ( < 0.001 and = 0.04, respectively) and developed a significantly fewer adenomas ( = 0.01). Moreover, a decrease in high-grade adenomas ( = 0.03) and adenomas with a diameter above 2 mm ( < 0.0001) was noted in ; mice. Further molecular analysis showed that gene inactivation in the small intestine and colon tissues of ; mice resulted in a significant suppression of transforming growth factor β2 (TGF-β2) protein ( ≤ 0.02) and mitogen-activated protein kinase (MAPK) phosphorylation ( ≤ 0.01).
CONCLUSIONS: These findings demonstrate the oncogenic role of KLK6 in the mutant -mediated intestinal tumorigenesis and suggest the utility of KLK6 for early diagnosis of colorectal tumors.