Fig. 7: PD173074 in combination with ETC-1002 significantly suppresses ONECUT2-mediated HCC metastasis.

A Protein levels of p-AMPKα, AMPKα, p-FGFR1, and FGFR1 were measured in ONECUT2-overexpressing PLC/PRF/5 cells after treatment with PD173074 (5 μM, 12 h), ETC-1002 (100 μM, 12 h) or PD173074 combined with ETC-1002 by western blotting. B Transwell assays were used to evaluate migration and invasion of the indicated cells. C Diagram of the administration strategies in vivo. One week after the orthotopic implantation, the nude mice were administered PD173074 (50 mg/kg), ETC-1002 (30 mg/kg) or PD173074 combined with ETC-1002. D–I PD173074 combined with ETC-1002 markedly inhibited ONECUT2-enhanced HCC metastasis. Representative bioluminescent imaging (D), bioluminescent signals (E), the incidence of pulmonary metastasis (F), number of pulmonary metastasis foci (G), overall survival (H), and H&E staining of the lungs (I) among four groups of nude mice treated with different administration strategies (n = 10 in each group) for 8 weeks following orthotopic implantation of PLC/PRF/5-ONECUT2 cells. Data are mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001. J Proposed model showing the role of ONECUT2 in facilitating HCC metastasis. FGF2 upregulates ONECUT2 expression via FGFR1/ERK/ELK1 signaling pathway. ONECUT2 facilitates HCC metastasis through transcriptionally upregulating FGF2 and ACLY expression. The combination of FGFR1 inhibitor with ACLY inhibitor dramatically suppresses ONECUT2-mediated HCC metastasis.