PO-179 Identification of C-Met and insulin receptor heterodimer as a mediator for hepatocellular carcinoma
ESMO Open(2018)
摘要
Introduction Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths and obesity is predicted to be the leading cause for HCC in the following decades. Hyperglycemia and hyperinsulinemia are the two obesity-related factors associated with poor prognosis and survival. Hepatocyte growth factor (HGF) receptor, c-Met overactivation is common and results in higher proliferation and metastasis of HCC cells and drug resistance. In HCC patients, c-Met activation is often observed in the absence of HGF. Material and methods Cells were starved for 24 hours before hyperglycemic (HG, 25 mM) and/or hyperinsulinemic (HI, 100 nM) induction. Lysates were analysed by western blotting using the antibodies detecting activatory phosphorylations of c-Met, IR, Erk 1/2 and Akt. Receptor dimerization was studied by coimmunoprecipitation and colocalization using live-cell imaging. c-Met(SU11274) and IR(HMPA-(AM)3) inhibitors were used to reverse the effects of activations. Tumour cell metabolism was analysed using Seahorse Analyzer with cells expressing predominantly either IR isoform A or B. Proliferation and adhesion capacities were investigated using real time cell analysis system xCELLigence for 96 hours. Tumour cell survival in HG/HI blood circulation was simulated by circulation under shear stress for 4 hours in a fluidic system. Migration and invasion are studied using Boyden chamber. Results and discussions c-Met expression and activation was elevated when induced by high glucose/insulin. Also c-Met and IR were found to form a heterodimer upon HG/HI induction which explains a mechanism of c-Met activation even when HGF is absent in the tumour microenvironment. Both IR isoforms A/B were found to colocalize with c-Met and mediate the effect. In the presence of inhibitors, receptor activations and colocalizations were disrupted. c-Met inhibition resulted in a shift in tumour cell metabolism; diminished glycolysis and oxidative phosphorylation, which offers a role for rendering the cells more aggressive. Elevated adhesion, proliferation, migration, invasion and survival were observed upon induction which are controlled by Erk 1/2 and Akt activations, reversed by c-Met inhibition. Conclusion Here we identified that obesity-related prognostic factors, hyperglycemia and hyperinsulinemia, increase invasive and metastatic capacity of HCC cells through transactivation of c-Met by IR, which might also be a mechanism for drug resistance and offer an approach for targeted therapy.
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关键词
insulin receptor heterodimer,hepatocellular carcinoma,insulin receptor,c-met
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