{Reference Type}: Journal Article
{Title}: ETS-1/c-Met drives resistance to sorafenib in hepatocellular carcinoma.
{Author}: Ma Y;Liu X;Tang X;
{Journal}: Am J Transl Res
{Volume}: 15
{Issue}: 2
{Year}: 2023
{Factor}: 3.94
{Abstract}: BACKGROUND: The purpose of this study was to clarify the molecular regulatory mechanism of c-Met up-regulated expression and elucidate the molecular mechanisms by which c-Met overexpression and activation drive progression and sorafenib resistance in hepatocellular carcinoma (HCC).
METHODS: 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 results. To determine the regulatory mechanisms and effects of c-Met on sorafenib resistance in HCC, c-Met expression and activation were down-regulated by siRNA and inhibitor in in vivo and vitro experiments, while a parental cell line (Huh-7) was transfected with the adenovirus that upregulated c-Met expression.
RESULTS: 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.
CONCLUSIONS: 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.