Abstract
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.
Highlights
Hepatocellular carcinoma (HCC) is the fifth most diagnosed malignancy and the second leading cause of cancer-related death worldwide (El-Serag, 2012)
The results demonstrated that Compound Phyllanthus urinaria L. (CP) exhibited obvious inhibitory activities on HepG2, SMMC7721 and Huh-7 cells in a dose-and time-dependent manner
We continued to investigate the inhibitory effects of CP on HBVassociated phenotypes of HCC cells
Summary
Hepatocellular carcinoma (HCC) is the fifth most diagnosed malignancy and the second leading cause of cancer-related death worldwide (El-Serag, 2012). Despite the improvement of conventional therapies for the comprehensive treatment of HCC, the 5-year survival rate of liver cancer is still lower than 5% due to postoperative recurrence and metastasis (Li et al, 2015). A high HBV-DNA load is positively associated with HCC recurrence and HBV reactivation is an independent risk factor of 10-year survival after resection of HBV-related HCC (Hung et al, 2008; Huang et al, 2013). The 5-year postoperative metastasis rate is up to 45.3%, which is most likely the cause of death in patients with HCC (Zhou et al, 1994). The suppression of metastasis is a promising therapeutic target for HBV-associated HCC, and revealing the underlying mechanisms can boost development of strategies against HBVassociated HCC
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