Cigarette smoke promotes sorafenib resistance in HCC via 14-3-3η (IMAGE)
Caption
Due to the insidious onset of HCC, most smokers have developed progressive HCC by the time they are diagnosed. Therefore, the tumors of smokers are usually continuously exposed to a microenvironment formed by cigarette compounds throughout the course from initiation to diagnosis of HCC (advanced stages). Based on this, we proposed the following innovative findings: during chronic exposure to cigarette compounds, a key “switch-like” molecule, 14-3-3η, was activated by an epigenetic accumulation mechanism of DNA demethylation. Anti-apoptosis, drug efflux, and neo-vascularization were the three pivotal biological processes involved. Specifically, 14-3-3η activated B-Raf/ERK via phosphorylation and then blocked the activation of the caspase cascade. Activated B-Raf/ERK/NF-κB also transcriptionally upregulated MDR1, ABCG2, VEGF, and G-CSF. These three processes together promote sorafenib resistance in HCC. Furthermore, we revealed the functions of ATO in reversing the above phenomenon. This study revealed the influences of cigarette compound-formed microenvironment on the progression of HCC and provided innovative theoretical basis for therapeutic strategies for advanced HCC.
Credit
Professor Yuan Li From Nanjing Medical University; Dr. Ming Jin From Fujian Medical University
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CC BY-NC