Kawasaki Rie, Kukimoto Iwao, Nishio Eiji, Otani Sayaka, Nishizawa Haruki, Maeda Yasuhiro, Iwata Aya, Fujii Takuma
Department of Gynecology, Fujita Health University, School of Medicine, Toyoake, Aichi, Japan.
Department of Obstetrics and Gynecology, Fujita Health University, School of Medicine, Toyoake, Aichi, Japan.
Front Cell Infect Microbiol. 2025 Jul 16;15:1589277. doi: 10.3389/fcimb.2025.1589277. eCollection 2025.
Cervical cancer is the fourth most common malignancy in women and is primarily caused by persistent infection with high-risk human papillomavirus (HPV). In addition, host immune responses, genetic factors, and lifestyle habits also have etiological roles. The cervicovaginal microbiome undergoes dynamic changes during menopause, which may be involved in the progression of cervical neoplasia. We aimed to elucidate the association between cervical microenvironmental changes and the progression of cervical neoplasia before and after menopause by integrating analyses of the cervical microbiome, related metabolites, cytokines, and microRNAs.
A total of 248 HPV-positive women with cervical neoplasia, including 17 with cervical intraepithelial neoplasia (CIN1), 80 with CIN2, 82 with CIN3, and 69 with squamous cell carcinoma (SCC), were enrolled. As normal controls, 48 HPV-negative healthy women were included. Each group was stratified based on the mean menopausal age of 50 years. Cervical mucus was analyzed according to the methods outlined below. The microbiota was profiled by 16S rRNA gene sequencing, metabolites were analyzed by ultra-HPLC-tandem mass spectrometry, RT-qPCR was used for miRNA expression analysis, and RANTES levels were quantified by multiplex bead array. Data analysis was performed using MicrobiomeAnalyst and MetaboAnalyst.
In the SCC group, and were the key bacterial genera among the younger group, while , , and were more prevalent in elderly group (LDA score > 4.5). We observed a consistent positive correlation between and xanthine in younger groups with CIN2 or worse ( < 0.0001). However, no such correlations were detected in elderly women. In addition, , , and showed significant positive correlation with nicotinic acid in younger women with SCC compared to the elderly women ( < 0.0001). In the younger SCC women, several metabolites were significantly elevated in groups with high expression levels of RANTES, miR-20b-5p, and miR-155-5p.
The cervical microbiome undergoes changes during menopause, and may influence disease progression by interacting with metabolites, cytokines, and miRNAs. These results highlight the potential for personalized medicine for cervical cancer that is tailored to different age groups.
宫颈癌是女性中第四常见的恶性肿瘤，主要由高危型人乳头瘤病毒（HPV）持续感染引起。此外，宿主免疫反应、遗传因素和生活习惯也具有病因学作用。宫颈阴道微生物群在绝经期间会发生动态变化，这可能与宫颈肿瘤的进展有关。我们旨在通过整合宫颈微生物群、相关代谢物、细胞因子和微小RNA的分析，阐明绝经前后宫颈微环境变化与宫颈肿瘤进展之间的关联。
共纳入248例HPV阳性的宫颈肿瘤女性，其中17例为宫颈上皮内瘤变（CIN1），80例为CIN2，82例为CIN3，69例为鳞状细胞癌（SCC）。作为正常对照，纳入48例HPV阴性的健康女性。每组根据平均绝经年龄50岁进行分层。按照以下所述方法对宫颈黏液进行分析。通过16S rRNA基因测序对微生物群进行分析，通过超高效液相色谱-串联质谱法分析代谢物，使用RT-qPCR进行miRNA表达分析，并通过多重微珠阵列对RANTES水平进行定量。使用MicrobiomeAnalyst和MetaboAnalyst进行数据分析。
在SCC组中，年轻组的关键细菌属为 和 ，而老年组中 、 和 更为普遍（线性判别分析得分>4.5）。我们在CIN2或更严重病变的年轻组中观察到 和黄嘌呤之间存在一致的正相关（<0.0001）。然而，在老年女性中未检测到此类相关性。此外，与老年女性相比，年轻SCC女性中 、 和 与烟酸呈显著正相关（<0.0001）。在年轻的SCC女性中，RANTES、miR-20b-5p和miR-155-5p高表达组中的几种代谢物显著升高。
宫颈微生物群在绝经期间会发生变化，并可能通过与代谢物、细胞因子和miRNA相互作用影响疾病进展。这些结果凸显了针对不同年龄组的宫颈癌个性化医疗的潜力。
