Compound Phyllanthus urinaria L. (CP) is a
traditional Chinese medicine (TCM) formula for
cancer treatment in the clinic, particularly during progression of
hepatitis B-associated
hepatocellular carcinoma (HBV-associated HCC). Nevertheless, its anti-metastatic action and mechanisms are not well elucidated. In this study, CP was found to exert remarkable inhibitory effects on the proliferation, migration and invasion of HBV-associated HCC cells. The following network and biological analyses predicted that CP mainly targeted
Caveolin-1 (Cav-1) to induce anti-metastatic effects, and Wnt/β-
catenin pathway was one of the core mechanisms of CP action against HBV-associated HCC. Further experimental validation implied that Cav-1 overexpression promoted
metastasis of HBV-associated HCC by stabilizing β-
catenin, while CP administration induced autophagic degradation of Cav-1, activated the Akt/GSK3β-mediated
proteasome degradation of β-
catenin via ubiquitination activation, and subsequently attenuated the
metastasis-promoting effect of Cav-1. In addition, the anti-
cancer and anti-metastatic action of CP was further confirmed by in vivo and ex vivo experiments. It was found that CP inhibited the
tumor growth and
metastasis of HBV-associated HCC in both mice
liver cancer xenograft and zebrafish
xenotransplantation models. Taken together, our study not only highlights the novel function of CP formula in suppressing
metastasis of HBV-associated HCC, but it also addresses the critical role of Cav-1 in mediating Akt/GSK3β/β-
catenin axis to control the late-phase of
cancer progression.