Fig 2: The effect of melatonin on cell migration and invasion in SCC-15 cells with or without FGF19 overexpression. The mRNA (A,B) and protein expression levels of FGF19/FGFR4 (C) after hFGF19 overexpression. The invasion and migration ability of cell was determined by trasnwell migration assays at 24 h (G), transwell invasion assays at 36 h (G) and wound healing at 12 h, 24 h, 36 h (E) (Scale bars: (E,G), 100 nm). Quantitative data from three independent experiments are shown in the right panels, respectively (D,F,H). * p < 0.05; ** p < 0.01, *** p < 0.001.

Fig 3: The association between circKCNN2 and the therapeutic effect of lenvatinib. (A) The proliferation of Huh7 and HepG2 cells were inhibited by different doses of lenvatinib. (B) The effect of lenvatinib treatment and circKCNN2 overexpression on the proliferation of Huh7 cells. (C) The effect of lenvatinib treatment and circKCNN2 overexpression on the apoptosis of Huh7 cells. (D) Lenvatinib treatment elevated the RNA level of circKCNN2 in Huh7 cells. The DMSO group served as a reference for normalization. (E) circKCNN2 and lenvatinib enhanced the expression of MBD2 in Huh7 cells. The group without treatment served as a reference for normalization. (F) The effect of circKCNN2 and lenvatinib on the protein levels of FRS2, FGF19, and FGFR4 in Huh7 and HepG2 cells. (G) The miR-520c-3p mimics and the knockdown of MBD2 can reverse the circKCNN2-induced downregulation of FGFR4. (H) The inherent levels of circKCNN2 in the two HCC organoids. Org543 served as a reference for normalization. (I) The effect of circKCNN2 overexpression on the cell growth of HCC organoids. (J) The effect of lenvatinib on the cell growth of HCC organoids. All the assays were performed at least three times. n = 3 for each group. *P < 0.05, **P < 0.01, ***P < 0.001

Fig 4: The mRNA and protein expression levels of FGF19/FGFR4 after FGF19 knocking down. The mRNA (A,B) and protein expression levels of FGF19/FGFR4 (C,D) after hFGF19 knocking down. The invasion and migration ability of cell was determined by trasnwell migration assays at 24 h (F), transwell invasion assays at 36 h (F) and wound healing at 12 h, 24 h, 36 h (E) (Scale bars: (E,G), 100 nm). Quantitative data from three independent experiments are shown in the bottom, respectively (G,H). * p < 0.05; ** p < 0.01, *** p < 0.001.