Tang Qing, Yang Ying, Sun Jia'nan
Department of Gynecology, Yantai Yuhuangding Hospital, No.20, Yuhuangding East Road, Yantai, 264000, China.
Hum Cell. 2025 Jun 19;38(4):119. doi: 10.1007/s13577-025-01246-3.
High-risk HPV subtypes impact the immune response in cervical cancer. Tumor-associated macrophages (TAMs) are well known to contribute to tumor development by regulating the immune response. This study aimed to analyze the mechanism of TAMs by the enhancer of zeste homolog 2 (EZH2) in HPV16 cervical cancer. The HPV16 cervical cancer cells, SiHa and CaSki, were treated with increasing concentrations of EZH2 inhibitor EPZ6438 (5, 10, 20, 40, 80 μM) for 24 h. The KDM6A expression is suppressed in a concentration-dependent manner when EZH2 activity is inhibited. Then, the cancer cells were transfected with pcDNA-control or pcDNA-KDM6A, and treated with the IC of EPZ6438. The cell viability, levels of IL-6 and CXCL1, and p-Akt(s473)/Akt proteins were measured. The PMA-treated THP-1 cells were induced into M2 macrophages by IL-4 and IL-13. The M2 macrophages were cocultured with the conditioned cancer cells to observe the M2 polarization. In vivo experiments, the effects of EZH2 inhibition on tumor growth were investigated in nude mice. EZH2 inhibition suppressed the cell viability and inflammatory response by suppressing KDM6A in HPV16 cervical cancer cells. KDM6A overexpression suppressed the effects of EZH2 inhibition on cell viability and inflammatory response. EZH2 inhibition in cancer cells suppressed the M2 macrophages, and its mechanism was related to the KDM6A-mediated inflammatory response. In nude mice models, EZH2 inhibition effectively reduced tumor growth by regulating KDM6A. EZH2 regulated the KDM6A-mediated inflammatory response, thus affecting the polarization of M2 macrophages, leading to tumor growth in HPV16 cervical cancer. This study provided an insight into the immune modulation of EZH2 in HPV16 cervical cancer.
高危型人乳头瘤病毒（HPV）亚型影响宫颈癌的免疫反应。众所周知，肿瘤相关巨噬细胞（TAM）通过调节免疫反应促进肿瘤发展。本研究旨在分析在HPV16宫颈癌中，zeste同源物2（EZH2）增强子对TAM的作用机制。用浓度递增的EZH2抑制剂EPZ6438（5、10、20、40、80μM）处理HPV16宫颈癌细胞SiHa和CaSki 24小时。当EZH2活性受到抑制时，赖氨酸特异性去甲基化酶6A（KDM6A）的表达呈浓度依赖性抑制。然后，用pcDNA-对照或pcDNA-KDM6A转染癌细胞，并用EPZ6438的半数抑制浓度（IC）处理。检测细胞活力、白细胞介素-6（IL-6）和CXC趋化因子配体1（CXCL1）水平以及磷酸化蛋白激酶B（p-Akt）（丝氨酸473位点）/蛋白激酶B（Akt）蛋白水平。用佛波酯（PMA）处理的人单核细胞白血病细胞系（THP-1）细胞通过白细胞介素-4（IL-4）和白细胞介素-13诱导为M2巨噬细胞。将M2巨噬细胞与条件培养基处理后的癌细胞共培养以观察M2极化。在体内实验中，研究了EZH2抑制对裸鼠肿瘤生长的影响。EZH2抑制通过抑制HPV16宫颈癌细胞中的KDM6A来抑制细胞活力和炎症反应。KDM6A过表达抑制了EZH2抑制对细胞活力和炎症反应的影响。癌细胞中的EZH2抑制抑制了M2巨噬细胞，其机制与KDM6A介导的炎症反应有关。在裸鼠模型中，EZH2抑制通过调节KDM6A有效降低肿瘤生长。EZH2调节KDM6A介导的炎症反应，从而影响M2巨噬细胞的极化，导致HPV16宫颈癌的肿瘤生长。本研究为EZH2在HPV16宫颈癌中的免疫调节作用提供了见解。
