Fig 1: Sorafenib increases the expression levels of multiple MT1 genes in cancer cells. a MT1 genes represent a significant fraction (6/35) of the genes found to be overexpressed by more than three-fold in Huh7 cells exposed to sorafenib (10 µM) for 9 h. b QPCR analysis of the mRNA encoding the main isoforms of MT1 in Huh7 cells exposed to sorafenib (10 µM) for 9 h. c Immunoblot analysis of the expression of the MT1 protein. Protein extracts were prepared from Huh7 cells treated for 4 to 18 h with 10 µM sorafenib. d MT1G mRNA levels were measured by QPCR in a panel of cancer cell lines and in primary human hepatocytes (PHH) exposed to sorafenib 10 µM for 9 h. *: p < 0.05 compared to control, n.s.: non-significant compared to control. e: MT1G mRNA levels analysis in Huh7 cells exposed to ZnCl2 100 µM and sorafenib (10 µM) for 18 h. f Analysis of MT1G mRNA levels by QPCR in Huh7 cell lines exposed to sorafenib or selected kinase inhibitors applied at pharmacological concentrations (selumetinib 1 µM, erlotinib 1 µM, vemurafenib 10 µM and rapamycin 1 µM) for 18 h. *: p < 0.05 compared to control
Fig 2: MT1 as a clinically-applicable biomarker. a: Evaluation of MT1G induction in five HCC tumour explants. Tumour slices were prepared from five surgically-resected HCC and maintained in culture for 18 h in control conditions or in the presence of sorafenib (10 µM). The levels of MT1G mRNA were evaluated by QPCR, and the values were used to calculate a ratio. b Levels of MT1 were measured in the sera of 20 patients with advanced HCC and treated with sorafenib. Serum MT1 values are presented before and after sorafenib treatment. * indicates p < 0.05 between the two series using paired Wilcoxon test. c MT1 concentration in the patient population with low serum concentrations of sorafenib (i.e. below the median) and the patient population with high serum concentrations of sorafenib (i.e. above the median). The graph is based on the calculated ratio of the serum values of MT1 measured after sorafenib treatment and MT1 before sorafenib treatment. n.s.: indicates a lack of significant difference between the two groups. d Kaplan-Meier analysis of the progression-free survival (PFS) of HCC patients receiving sorafenib. Patients were divided into two groups: one with the lowest and one with the highest induction of MT1 upon sorafenib treatment (based on the calculation of the ratio of MT1 before/MT1 after sorafenib treatment, and using the median value as cut-off). e Kaplan-Meier analysis of the overall survival (OS) of HCC patients receiving sorafenib
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