Kallikrein-Related Peptidase 6 Contributes to Murine Intestinal Tumorigenesis Driven by a Mutant Gene.

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.