ABSTRACT
PURPOSE: Emerging evidence suggests that vaginal micro-environment disorder is closely related to the development of cervical lesions. Low-grade cervical intraepithelial neoplasia (CIN1), as an early stage of cervical lesions, exhibits a high risk of progressing to high-grade lesions or even cervical cancer. However, the effect of vaginal micro-environment on the malignant prognosis of CIN1 remains uncertain. METHODS: A total of 504 patients diagnosed with CIN1 by pathology, who were from the population-based cohorts established in Shanxi Province, China, were enrolled and followed up for 2 years. Micro-environmental factors such as vaginal pH, cleanliness, hydrogen peroxide (H2O2), ß-glucuronidase (GUSB), leucocyte esterase (LE), and sialidase (SNA) were detected to evaluate their effect on the malignant prognosis of CIN1. RESULTS: Abnormal vaginal pH (HR = 1.472, 95%CI 1.071-2.022), cleanliness (HR = 1.446, 95%CI 1.067-1.960), H2O2 (HR = 1.525, 95%CI 1.155-2.013), GUSB (HR = 1.739, 95%CI 1.235-2.448), LE (HR = 1.434, 95%CI 1.038-1.981), and SNA (HR = 1.411, 95%CI 1.065-1.870) could promote a higher incidence of CIN1 malignant prognosis, and the combined effects of these micro-environmental factors resulted in a nearly twofold increased risk (HR = 2.492, 95%CI 1.773-3.504) compared to any single factor alone, especially under the high-risk human papillomavirus (HR-HPV) infection. Notably, the cumulative incidence of malignant prognosis for CIN1 gradually increased during the early follow-up period, reaching its peak at approximately 8 months, and then stabilizing. CONCLUSION: Vaginal micro-environment disorder could promote CIN1 malignant prognosis, particularly in HR-HPV-infected women. Taking micro-environmental factors as the breakthrough, our study provides a feasible vision for preventing early stage cervical lesions.
ABSTRACT
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
