Zhang Ruiyang, Hou Feifei, Gan Jianguo, Zhang Lishen, Yang Dan, Yang Fan, Xia Xiaoqiang, Chen Qianming, Bian Ce, Feng Xiaodong
West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan Province.
Key Laboratory of Oral Biomedical Research of Zhejiang Province, Affiliated Stomatology Hospital, Zhejiang University School of Stomatology, Hangzhou, Zhejiang Province.
Anticancer Drugs. 2025 Jul 1;36(6):468-477. doi: 10.1097/CAD.0000000000001711. Epub 2025 May 7.
The human papillomavirus (HPV) is implicated in multiple lethal cancers, although it is more sensitive to certain therapies than HPV-negative cancers. Therefore, the development of more targeted therapeutic strategies is imperative. The HPV oncogenes E6/E7 are ideal targets for HPV-positive cancer, but there are no clinical strategies that have been proven to effectively target E6/E7. Notably, metformin significantly inhibits E6/E7 expression; however, the underlying mechanism and therapeutic potential remain unclear, limiting its clinical translation. Cell Counting Kit-8, ethynyl-2'-deoxyuridine, and terminal-deoxynucleotidyl transferase-mediated Nick end labeling assays were conducted to evaluate the effects of metformin on cell viability, proliferation, and apoptosis. Quantitative real-time PCR, western blotting, and immunofluorescence assays were performed to determine changes in E6/E7 and p53 expression levels following metformin treatment. Patient-derived organoids and in-vivo xenograft models were constructed to evaluate the anticancer activity of metformin against HPV-positive cancer. Our research demonstrated enhanced sensitivity of HPV-positive cancer cells to metformin. Mechanistic studies have revealed that metformin exerts anticancer effects by inhibiting E6/E7 expression, which is associated with p53 reactivation. Furthermore, we substantiated the anticancer potential of metformin in HPV-positive patient-derived organoids and in-vivo tumor models. Our study focused on the mechanism underlying the enhanced responsiveness of HPV-positive cancer to metformin, highlighting the clinical potential of metformin as a targeted therapeutic strategy for HPV-positive cancer.
人乳头瘤病毒（HPV）与多种致命癌症相关，尽管它比HPV阴性癌症对某些疗法更敏感。因此，开发更具针对性的治疗策略势在必行。HPV癌基因E6/E7是HPV阳性癌症的理想靶点，但尚无已被证明能有效靶向E6/E7的临床策略。值得注意的是，二甲双胍可显著抑制E6/E7表达；然而，其潜在机制和治疗潜力仍不清楚，这限制了它的临床应用。进行了细胞计数试剂盒-8、乙炔基-2'-脱氧尿苷和末端脱氧核苷酸转移酶介导的缺口末端标记分析，以评估二甲双胍对细胞活力、增殖和凋亡的影响。进行了定量实时PCR、蛋白质免疫印迹和免疫荧光分析，以确定二甲双胍治疗后E6/E7和p53表达水平的变化。构建了患者来源的类器官和体内异种移植模型，以评估二甲双胍对HPV阳性癌症的抗癌活性。我们的研究表明HPV阳性癌细胞对二甲双胍的敏感性增强。机制研究表明，二甲双胍通过抑制E6/E7表达发挥抗癌作用，这与p53的重新激活有关。此外，我们证实了二甲双胍在HPV阳性患者来源的类器官和体内肿瘤模型中的抗癌潜力。我们的研究聚焦于HPV阳性癌症对二甲双胍反应增强的潜在机制，突出了二甲双胍作为HPV阳性癌症靶向治疗策略的临床潜力。
