A research team led by Professor Yuan Li at Nanjing Medical University published a research paper entitled "A Cigarette Compound-Induced Tumor Microenvironment Promotes Sorafenib Resistance in Hepatocellular Carcinoma via the 14-3-3η-Modified Tumor-Associated Proteome" in the Chinese Medical Journal. This work provides valuable insights into the role of smoking in HCC progression and drug resistance, offering potential therapeutic targets for overcoming sorafenib resistance.
The study began with an analysis of clinical follow-up data from HCC patients, revealing that smokers exhibited significantly poorer survival outcomes compared to non-smokers. Building on this finding, a sorafenib-resistant HCC cell model induced by cigarette smoking extract (CSE) was established. These results indicate that cigarette compound exposure continuously activates 14-3-3η via epigenetic accumulation of DNA demethylation, and that, the expression level/promoter methylation degree of 14-3-3η influenced the efficacy of sorafenib. Sorafenib plays a pluripotent role mainly by regulating the phosphorylation of multiple-targeted tyrosine kinases and mitigating angiogenesis. By integrating findings from phospho-antibody and angiogenesis antibody arrays, the authors revealed that 14-3-3η activates the B-Raf/ERK signaling pathway and regulates a cascade of downstream factors. This activation enhances anti-apoptotic mechanisms, accelerates drug efflux, and promotes neo-angiogenesis, and these three critical processes synergistically contribute to the development of sorafenib resistance in HCC. Finally, in a subcutaneous tumour xenograft model using nude mice, authors further investigated the expression levels of the aforementioned key molecules and evaluated the therapeutic efficacy of arsenic trioxide (ATO). The results demonstrated that ATO monotherapy significantly suppressed 14-3-3η and its downstream targets, while also inhibiting angiogenesis and promoting apoptosis. Notably, the combination of ATO and sorafenib exhibited a synergistic effect, leading to an even more pronounced suppression of tumor progression.
In this study, we systematically elucidated the key molecular mechanisms underlying sorafenib resistance in HCC induced by chronic smoking exposure, as well as the associated regulatory biological processes. Furthermore, we explored the potential therapeutic effects of traditional Chinese medicine components targeting these critical pathways. The findings not only deepen the theoretical understanding of drug resistance mechanisms in HCC but also provide a robust scientific foundation and practical guidance for optimizing strategies to prevent and control malignant tumors. Additionally, this research opens new avenues for the clinical prevention and treatment of HCC, offering promising applications for future therapeutic interventions.
