The role of the proprotein convertase furin in cancer

Furin, together with six other members (PC1/3, PC2, PC4, PACE4, PC5/6 and PC7), constitutes the proprotein convertase (PC) family that is responsible for the cleavage and activation of various protein precursors in cells. Maturation of several of these precursors is required for various processes of tumor initiation, progression and metastasis. However, different cancer types show distinguish expression trends of furin compared to paired normal tissues in TCGA (The Cancer Genome Atlas) database. These findings indicate that furin could function as either an oncogene or a onco-suppresser gene. Therefore, the purpose of this thesis is to know the oncogenic or tumor suppressive role of furin in different cancer types including colorectal cancer and breast cancer. In first project, we investigate the role of furin in colorectal cancer. We show that genetic inactivation of furin suppresses tumorigenic growth, proliferation, and migration in KRAS or BRAF mutant CRC cell lines but not in wild-type KRAS and BRAF cells. In a mouse xenograft model, these KRAS or BRAF mutant cells lacking furin displayed reduced growth and angiogenesis, and increased apoptosis. Mechanistically, furin inactivation prevents the processing of various protein pecursors including proIGF1R, proIR, proc-MET, proTGF-β1 and NOTCH1 leading to potent and durable ERK-MAPK pathway suppression in KRAS or BRAF mutant cells. Furthermore, we identified genes involved in activating the ERK-MAPK pathway, such as PTGS2, which are downregulated in the KRAS or BRAF mutant cells after furin inactivation but upregulated in wild-type KRAS and BRAF cells. Analysis of human colorectal tumor samples reveals a positive correlation between enhanced furin expression and KRAS or BRAF expression. These results indicate that furin plays an oncogenic role in KRAS or BRAF-associated ERK-MAPK pathway activation and tumorigenesis, providing a potential target for personalized treatment. In the second and third project, we investigate the role of furin in breast cancer. We first establish oncogene-induced triple negative breast cancer (TNBC) mouse model and breed it to transgenic mouse model without furin either in T cells or in mammary gland. In T cell-specific furin deficient TNBC mice, mammary tumor growth and lung metastasis are significantly inhibited. Disruption of furin in T cells in these mice led to a decreased peripheral and tumor-infiltrating Tregs. As a consequence, tumor-infiltrating CD8+ T cells showed a strong proliferative capacity and upregulated expression of IFN-γ and TNF-α. In these mice the repressed tumor growth was associated with induced apoptosis, which led to reduced lung metastases formation. There is also the case in mammary epithelial cells-specific furin deficient TNBC mice. Taken together, these finding reveal the potential therapeutic benefit of targeting furin in TNBC.

Jaar van publicatie:2020

Toegankelijkheid:Closed