Department of Epidemiology, School of Public Health, Shanxi Medical University, Taiyuan, 030000, China.
J Cancer Res Clin Oncol. 2023 Dec;149(19):17371-17381. doi: 10.1007/s00432-023-05453-z. Epub 2023 Oct 16.
Convincing studies demonstrated that cervicovaginal microbiota disorder and toll-like receptor 9 (TLR9) high expression were related to cervical carcinogenesis. However, the effects of cervicovaginal microbiota integration TLR9 in cervical cancerization are unclear. Based on the biological basis that unmethylated cytosine-phosphate-guanine (CpG) motifs of bacteria could activate TLR9, we explored the effects of cervicovaginal microbiota disorder and CpG motif-TLR9 axis change in cervical carcinogenesis.
A total of 341 participants, including 124 normal cervical (NC), 90 low-grade cervical intraepithelial neoplasia (CIN1), 78 high-grade cervical intraepithelial neoplasia (CIN2/3) and 49 squamous cervical cancer (SCC), diagnosed by pathology were enrolled in the study. Here, metagenomic shotgun sequencing was used to reveal cervicovaginal microbiota characteristics, and TLR9 protein was detected by western blotting.
Our results showed that the diversity of cervicovaginal microbiota gradually increased along with the poor development of cervical lesions, showing the abundance of Lactobacillus crispatus and Lactobacillus iners decreased, while the abundance of pathogenic bacteria gradually increased. The level of TLR9 expression was gradually increased with cervicovaginal microbiota diversity increasing, the abundance of Lactobacillus decreasing, and we found a positive correlation dependency relationship (r = 0.384, P = 0.002) between TLR9 and GTCGTT motif content. Stratified analysis based on HPV16 infection, we found that the characteristics of cervicovaginal microbiota and increased TLR9 expression were also closely related to HPV16 infection.
Cervicovaginal microbiota dysbiosis might lead to the CpG motif increased, which was closely associated with TLR9 high expression, and ultimately might promote the progression of cervical lesions.
有说服力的研究表明，宫颈阴道微生物群失调和 Toll 样受体 9（TLR9）高表达与宫颈癌的发生有关。然而，宫颈阴道微生物群整合 TLR9 在宫颈癌形成中的作用尚不清楚。基于细菌未甲基化胞嘧啶-磷酸-鸟嘌呤（CpG）基序可激活 TLR9 的生物学基础，我们探讨了宫颈阴道微生物群失调和 CpG 基序-TLR9 轴变化在宫颈癌形成中的作用。
共纳入 341 名患者，包括 124 名正常宫颈（NC）、90 名低级别宫颈上皮内瘤变（CIN1）、78 名高级别宫颈上皮内瘤变（CIN2/3）和 49 名宫颈鳞癌（SCC），所有患者均经病理诊断。本研究采用宏基因组鸟枪法测序揭示宫颈阴道微生物群特征，采用 Western blot 检测 TLR9 蛋白。
我们的结果表明，随着宫颈病变的进展，宫颈阴道微生物群的多样性逐渐增加，表现为 L. crispatus 和 L. iners 的丰度降低，而致病菌的丰度逐渐增加。TLR9 表达水平随着宫颈阴道微生物群多样性的增加、L. 的减少而逐渐升高，我们发现 TLR9 与 GTCGTT 基序含量之间存在正相关关系（r=0.384，P=0.002）。基于 HPV16 感染的分层分析，我们发现宫颈阴道微生物群特征和 TLR9 表达增加也与 HPV16 感染密切相关。
宫颈阴道微生物群失调可能导致 CpG 基序增加，这与 TLR9 高表达密切相关，最终可能促进宫颈病变的进展。
