PRSS8 suppresses colorectal carcinogenesis and metastasis

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• The serine protease PRSS8 (Prostasin) has known physiological roles, but its specific involvement in cancer development remains largely undefined.
• Understanding PRSS8's function is crucial for identifying new therapeutic targets in cancer treatment.

Purpose of the Study:

• To investigate the role of PRSS8 in colorectal cancer initiation, progression, and metastasis.
• To elucidate the molecular mechanisms underlying PRSS8's function in the context of cancer.

Main Methods:

• Development and characterization of a conditional knockout Prss8 mouse model (Prss8^fl/fl, p-Villin-Cre⁺).
• In vivo studies using nude mice to assess cancer cell growth and metastasis.
• In vitro assays including migration, invasion, colony formation, and tumor sphere formation.
• Gene profiling, gene set enrichment analysis, TCGA data mining, and immunohistochemical staining.

Main Results:

• Prss8 gene deficiency in mice resulted in spontaneous colitis, rectal inflammation, and later development of intestinal tumors, associated with altered cell proliferation, migration, and differentiation.
• Increased PRSS8 expression suppressed cancer cell growth, metastasis, migration, invasion, and colony formation in vitro and in vivo.
• Decreased PRSS8 expression promoted malignancies in both experimental settings.
• Mechanistic studies indicated that PRSS8 targets the Wnt/β-catenin, epithelial-mesenchymal transition, and stem cell signaling pathways.

Conclusions:

• PRSS8 functions as a novel tumor suppressor in the context of colorectal cancer.
• PRSS8 plays a critical role in suppressing colorectal carcinogenesis and metastasis by modulating key signaling pathways.