ETS-1/c-Met drives resistance to sorafenib in hepatocellular carcinoma

The

c-Met overexpression and activation is an essential mechanism of sorafenib resistance in HCC. Combination therapy of sorafenib plus c-Met inhibitor overcame the resistance of sorafenib-targeted therapy for HCC.

The resistance index was calculated. Bioinformatic techniques were applied to predict the transcription factors that bind and their binding sites on the c-Met promoter. Chromatin immunoprecipitation assays were implemented to verify the prediction

c-Met expression was increased in HCC sorafenib-resistant cells. Functional findings suggested that c-Met overexpression and activation drive HCC tumor progression and sorafenib resistance by promoting cell proliferation, migration, and stopping apoptosis. Molecular mechanism findings demonstrated that the MEK/ERK signaling pathway activated the expression and activity of ETS-1 mediated by p-ERK, which led to its binding to the c-Met gene promoter and upregulation of c-Met transcriptional expression. The activation of the HGF/c-Met pathway drives sorafenib resistance in HCC cells by activating the Ras/Raf/ERK and PI3K/Akt signaling pathways, which regulate biologic processes, including cell proliferation, migration and anti-apoptosis.