| First Author | Georgieva TG | Year | 2024 |
| Journal | Cancers (Basel) | Volume | 16 |
| Issue | 22 | PubMed ID | 39594797 |
| Mgi Jnum | J:358839 | Mgi Id | MGI:7783965 |
| Doi | 10.3390/cancers16223842 | Citation | Georgieva TG, et al. (2024) Kallikrein-Related Peptidase 6 Contributes to Murine Intestinal Tumorigenesis Driven by a Mutant Adenomatous polyposis coli Gene. Cancers (Basel) 16(22) |
| abstractText | 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 Adenomatous polyposis coli (APC) tumor suppressor gene. A first analysis of KLK6 expression in the intestinal tract of Apc-mutant multiple intestinal neoplasia (Apc(Min/+)) mice revealed up to four-fold induction of Klk6 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 Apc-mutant intestinal and colon tumorigenesis, we engineered a mouse with floxed alleles of the Klk6 gene (Klk6(lox/lox)) and crossed it with a mouse expressing the truncated APC protein under control of the intestinal tract-specific human CDX2P9.5-NLS Cre transgene (CPC;Apc(fl/fl);Klk6(+/+)). We found that CPC;Apc(fl/fl) mice with disrupted Klk6 gene expression (CPC;Apc(fl/fl);Klk6(fl/fl)) had a significantly smaller average size of the small intestinal and colon crypts (p < 0.001 and p = 0.04, respectively) and developed a significantly fewer adenomas (p = 0.01). Moreover, a decrease in high-grade adenomas (p = 0.03) and adenomas with a diameter above 2 mm (p < 0.0001) was noted in CPC;Apc(fl/fl);Klk6(fl/fl) mice. Further molecular analysis showed that Klk6 gene inactivation in the small intestine and colon tissues of CPC;Apc(fl/fl);Klk6(fl/fl) mice resulted in a significant suppression of transforming growth factor beta2 (TGF-beta2) protein (p </= 0.02) and mitogen-activated protein kinase (MAPK) phosphorylation (p </= 0.01). CONCLUSIONS: These findings demonstrate the oncogenic role of KLK6 in the mutant Apc-mediated intestinal tumorigenesis and suggest the utility of KLK6 for early diagnosis of colorectal tumors. |
