image: 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
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.
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Reference
DOI: https://doi.org/10.1097/CM9.0000000000003851
About Yuan Li from Nanjing Medical University
Yuan Li, PhD, Professor, Doctoral Supervisor. Member of Biomarker Committee of Chinese Society of Environmental Mutagens, and a member of the Chinese Medicine Pharmacology Committee of Jiangsu Pharmacology Society. Main research area: Mechanisms of chronic liver disease process and precise prevention/intervention.
Funding information
This work was supported by grants from the National Natural Science Foundation of China (Nos. 81961160708 and 82270653), the Major Projects of Science and Technology Development Fund of Nanjing Medical University (No. NMUD2019008), the Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), Jiangsu Provincial Medical Youth Talent (No. QNRC2016672), the Public Welfare Application Research Program of Huzhou (Nos. 2023GZ85 and 2021GY32), the Graduate Research and Innovation Projects of Jiangsu Province (No. KYCX22-1812), the High-Level Talents Research Start-Up Project of Fujian Medical University (No. XRCZX2024032), and the young and middle-aged teacher education research project of Fujian Province (No. JAT241033).
Journal
Chinese Medical Journal
Article Title
A cigarette compound-induced tumor microenvironment promotes sorafenib resistance in hepatocellular carcinoma via the 14-3-3η-modified tumor-associated proteome
Article Publication Date
26-Nov-2025