Liu Wenbin, Cai Shiliang, Pu Rui, Li Zixiong, Liu Donghong, Zhou Xinyu, Yin Jianhua, Chen Xi, Chen Liping, Wu Jianfeng, Tan Xiaojie, Wang Xin, Cao Guangwen
Department of Epidemiology, Second Military Medical University, 800 Xiangyin Rd., Shanghai 200433, China.
Department of Liver Cancer Surgery, Third Affiliated Hospital, Second Military Medical University, Shanghai 200433, China.
Cancers (Basel). 2022 Jul 4;14(13):3274. doi: 10.3390/cancers14133274.
This study aimed to elucidate the effects and underlying mechanisms of hepatitis B virus (HBV) preS mutations on hepatocarcinogenesis. The effect of the preS mutations on hepatocellular carcinoma (HCC) occurrence was evaluated using a prospective cohort study with 2114 HBV-infected patients, of whom 612 received antiviral treatments. The oncogenic functions of HBV preS mutations were investigated using cancer cell lines and () mouse models. RNA-sequencing and microarray were applied to identify key molecules involved in the mutant-induced carcinogenesis. Combo mutations G2950A/G2951A/A2962G/C2964A and C3116T/T31C significantly increased HCC risk in patients without antiviral treatment, whereas the preS2 deletion significantly increased HCC risk in patients with antiviral treatment. In mice, the preS1/preS2/S mutants induced a higher rate of tumor and higher serum levels of inflammatory cytokines than did wild-type counterpart. The preS1/preS2/S mutants induced altered gene expression profiles in the inflammation- and metabolism-related pathways, activated pathways of endoplasmic reticulum (ER) stress, affected the response to hypoxia, and upregulated the protein level of STAT3. Inhibiting the STAT3 pathway attenuated the effects of the preS1/preS2/S mutants on cell proliferation. G2950A/G2951A/A2962G/C2964A, C3116T/T31C, and preS2 deletion promote hepatocarcinogenesis via inducing ER stress, metabolism alteration, and STAT3 pathways, which might be translated into HCC prophylaxis.
本研究旨在阐明乙型肝炎病毒（HBV）前S区突变对肝癌发生的影响及潜在机制。采用前瞻性队列研究，对2114例HBV感染患者（其中612例接受抗病毒治疗）评估前S区突变对肝细胞癌（HCC）发生的影响。利用癌细胞系和（）小鼠模型研究HBV前S区突变的致癌功能。应用RNA测序和微阵列技术鉴定参与突变诱导致癌过程的关键分子。组合突变G2950A/G2951A/A2962G/C2964A和C3116T/T31C显著增加未接受抗病毒治疗患者的HCC风险，而前S2区缺失显著增加接受抗病毒治疗患者的HCC风险。在小鼠中，前S1/前S2/S突变体诱导的肿瘤发生率和血清炎症细胞因子水平高于野生型对照。前S1/前S2/S突变体在炎症和代谢相关途径中诱导基因表达谱改变，激活内质网（ER）应激途径，影响缺氧反应，并上调STAT3蛋白水平。抑制STAT3途径可减弱前S1/前S2/S突变体对细胞增殖的影响。G2950A/G2951A/A2962G/C2964A、C3116T/T31C和前S2区缺失通过诱导ER应激、代谢改变和STAT3途径促进肝癌发生，这可能转化为HCC的预防措施。
