Depletion of VPS35 attenuates metastasis of hepatocellular carcinoma by restraining the Wnt/PCP signaling pathway

Abstract

Vesicle Protein Sorting 35 (VPS35) is a novel oncogene that promotes tumor growth through the PI3K/AKT signaling in hepatocellular carcinoma (HCC). However, the role of VPS35 in HCC metastasis and the underlying mechanisms remain largely unclear. In this study, we observed that overexpression of VPS35 enhanced hepatoma cell invasion and metastasis by inducing epithelial–mesenchymal transition (EMT)-related gene expression. Conversely, knockout of VPS35 significantly inhibited hepatoma cell migration and invasion. Furthermore, depletion of VPS35 decreased the lung metastasis of HCC in nude mice. By transcriptome analysis, we determined that VPS35 promoted HCC metastasis by activating the Wnt/non-canonical planar cell polarity (PCP) pathway. Mechanistically, VPS35 activated the PCP pathway by regulating membrane sorting and trafficking of Frizzled-2 (FZD2) and ROR1 in hepatoma cells. Collectively, our results indicate that VPS35 promotes HCC metastasis via enhancing the Wnt/PCP signaling, thus providing a potential prognostic marker and therapeutic target for HCC.

Keywords

• Epithelial–mesenchymal transition
• Hepatocellular carcinoma (HCC)
• Metastasis
• Retromer complex
• VPS35
• Wnt/PCP signaling pathway