Low SVEP1 in intrahepatic cholangiocarcinoma mediates phenotype switching-driven metastasis by Jag2/Notch1/Hes5

Intrahepatic cholangiocarcinoma (ICC) is a distinct and increasingly prevalent subtype of cholangiocarcinoma arising from the epithelial cells of the intrahepatic bile ducts. Its molecular diversity contributes to its highly aggressive nature and resistance to chemotherapy. SVEP1 (sushi, Von Willebrand factor type A, EGF, and pentaxin) is a multi-domain extracellular matrix (ECM) protein that is vital for embryogenesis, cell-cell adhesion, and the maintenance of epidermal differentiation. However, the specific effect of SVEP1 on the occurrence and progression of ICC remains poorly understood. Therefore, this study aims to examine the role of SVEP1 in ICC. We first identified SVEP1 using high-throughput RNA sequencing in two groups of patients with ICC with different disease-free survival rates. We further analyzed the expression pattern of SVEP1 in ICC using various public datasets and clinical tissue samples, exploring the correlation between SVEP1 depletion and ICC clinical prognosis. The regulatory role of SVEP1 depletion in ICC progression was studied using in vitro and in vivo experiments. We found that decreased SVEP1 expression positively correlates with early recurrence and shorter overall survival in ICC. Moreover, SVEP1 downregulation was correlated with multiple poor prognostic parameters, including positive lymph nodes, satellite nodes, and high Ki-67 expression. Downregulated SVEP1 expression promoted ICC cell proliferation, chemotactic migration, and invasion in vitro, as well as tumor growth and lung metastasis in vivo. These effects were mediated by EMT phenotype switching through the activation of the Jag2/Notch1/Hes5 pathway. Our findings enhance the understanding of the novel mechanisms driving ICC progression and metastasis, suggesting that SVEP1 is a potential biomarker for ICC diagnosis.