<scp>KLK7</scp> overexpression promotes an aggressive phenotype and facilitates peritoneal dissemination in colorectal cancer cells

Colorectal cancer (CRC) incidence and mortality continue to rise globally and new prognostic biomarkers are required for the development of targeted therapies. Several studies have suggested that tissue kallikrein-related peptidases (KLKs), including KLK7, contribute to tumorigenesis. We previously demonstrated KLK7's tumor-promoting role both in vitro and in vivo, but its role in CRC metastasis remains unclear. Here, using the Cancer Genome Atlas (TCGA), we confirmed that KLK7 expression is upregulated in advanced stages of CRC and its association with shorter progression-free survival (PFS) of patients. To further understand the role of KLK7 in CRC metastasis, we assessed its expression in ascites from CRC patients with peritoneal metastasis (PM), investigated cell behavior following KLK7 overexpression, and examined its role in metastasis using a mouse model. High KLK7 levels were found in malignant ascites, but not in benign ascites. In xenograft models, KLK7-overexpressing cells increased PM and exhibited higher Peritoneal Cancer Index (PCI) scores compared to controls. In vitro, KLK7 overexpression in HT29-D4 human colon cancer cells significantly enhanced cell proliferation, colony formation, migration, spheroid formation, and adhesion to extracellular matrix proteins. Additionally, KLK7 overexpression altered cell morphology, upregulated moesin (MSN) and integrin subunits, suggesting cytoskeletal remodeling and matrix interactions. Taken together, these findings suggest that KLK7 is a driver of CRC progression and could serve as a potential prognostic marker for aggressive forms of CRC.