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Journal of Cancer Research and Clinical Oncology

Erschienen in:

16.10.2023 | Research

Cervicovaginal microbiota disorder combined with the change of cytosine phosphate guanine motif- toll like receptor 9 axis was associated with cervical cancerization

verfasst von: Xiao Zheng, Nan Hu, Jiamin Liu, Kailu Zhao, Huimin Li, Jiahao Wang, Mingxuan Zhang, Le Zhang, Li Song, Yuanjing Lyu, Meng Cui, Ling Ding, Jintao Wang

Erschienen in: Journal of Cancer Research and Clinical Oncology | Ausgabe 19/2023

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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.

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Anahtar MN, Gootenberg DB, Mitchell CM, Kwon DS (2018) Cervicovaginal Microbiota and Reproductive Health: The Virtue of Simplicity. Cell Host Microbe 23(2):159–168. https://doi.org/10.1016/j.chom.2018.01.013CrossRefPubMed

Anton L, Ferguson B, Friedman ES, Gerson KD, Brown AG, Elovitz MA (2022) Gardnerella vaginalis alters cervicovaginal epithelial cell function through microbe-specific immune responses. Microbiome 10(1):119. https://doi.org/10.1186/s40168-022-01317-9CrossRefPubMedPubMedCentral

Bhatla N, Aoki D, Sharma DN, Sankaranarayanan R (2021) Cancer of the cervix uteri: 2021update. Int J Gynaecol Obstet 155 Suppl 1(Suppl 1):28–44. https://doi.org/10.1002/ijgo.13865CrossRef

Chen Y, Qiu X, Wang W et al (2020) Human papillomavirus infection and cervical intraepithelial neoplasia progression are associated with increased vaginal microbiome diversity in a Chinese cohort. BMC Infect Dis 20(1):629. https://doi.org/10.1186/s12879-020-05324-9CrossRefPubMedPubMedCentral

Das S, Bhattacharjee MJ, Mukherjee AK, Khan MR (2023) Recent advances in understanding of multifaceted changes in the vaginal microenvironment: implications in vaginal health and therapeutics. Crit Rev Microbiol 49(2):256–282. https://doi.org/10.1080/1040841x.2022.2049696CrossRefPubMed

Daud II, Scott ME, Ma Y, Shiboski S, Farhat S, Moscicki AB (2011) Association between toll-like receptor expression and human papillomavirus type 16 persistence. Int J Cancer 128(4):879–886. https://doi.org/10.1002/ijc.25400CrossRefPubMedPubMedCentral

Davakis S, Kapelouzou A, Liakakos T et al (2022) The Role of Toll-like Receptors in Esophageal Cancer. Anticancer Res 42(6):2813–2818. https://doi.org/10.21873/anticanres.15762CrossRefPubMed

Di Pietro M, Filardo S, Porpora MG, Recine N, Latino MA, Sessa R (2018) HPV/Chlamydia trachomatis co-infection: metagenomic analysis of cervical microbiota in asymptomatic women. New Microbiol 41(1):34–41PubMed

Dong B, Huang Y, Cai H et al (2022) Prevotella as the hub of the cervicovaginal microbiota affects the occurrence of persistent human papillomavirus infection and cervical lesions in women of childbearing age via host NF-κB/C-myc. J Med Virol 94(11):5519–5534. https://doi.org/10.1002/jmv.28001CrossRefPubMed

Ghosh A, Dasgupta A, Bandyopadhyay A et al (2015) A study of the expression and localization of toll-like receptors 2 and 9 in different grades of cervical intraepithelial neoplasia and squamous cell carcinoma. Exp Mol Pathol 99(3):720–724. https://doi.org/10.1016/j.yexmp.2015.11.015CrossRefPubMed

Häcker G, Redecke V, Häcker H (2002) Activation of the immune system by bacterial CpG-DNA. Immunology 105(3):245–251. https://doi.org/10.1046/j.0019-2805.2001.01350.xCrossRefPubMedPubMedCentral

Hao Y, Yuan JL, Abudula A, Hasimu A, Kadeer N, Guo X (2014) TLR9 expression in uterine cervical lesions of Uyghur women correlate with cervical cancer progression and selective silencing of human papillomavirus 16 E6 and E7 oncoproteins in vitro. Asian Pacific J Cancer Prev : APJCP 15(14):5867–5872. https://doi.org/10.7314/apjcp.2014.15.14.5867CrossRef

Hartmann G, Krieg AM (2000) Mechanism and function of a newly identified CpG DNA motif in human primary B cells. J Immunol 164(2):944–53. https://doi.org/10.4049/jimmunol.164.2.944CrossRefPubMed

Hasimu A, Ge L, Li QZ, Zhang RP, Guo X (2011) Expressions of Toll-like receptors 3, 4, 7, and 9 in cervical lesions and their correlation with HPV16 infection in Uighur women. Chin J Cancer 30(5):344–350. https://doi.org/10.5732/cjc.010.10456CrossRefPubMedPubMedCentral

Iwasaki A, Medzhitov R (2010) Regulation of adaptive immunity by the innate immune system. Science 327(5963):291–295. https://doi.org/10.1126/science.1183021CrossRefPubMedPubMedCentral

Kang GU, Jung DR, Lee YH et al (2021) Potential Association between Vaginal Microbiota and Cervical Carcinogenesis in Korean Women: A Cohort Study. Microorganisms 9(2):294. https://doi.org/10.3390/microorganisms9020294CrossRefPubMedPubMedCentral

Kant R, de Vos WM, Palva A, Satokari R (2014) Immunostimulatory CpG motifs in the genomes of gut bacteria and their role in human health and disease. J Med Microbiol 63(Pt 2):293–308. https://doi.org/10.1099/jmm.0.064220-0CrossRefPubMed

Kumagai Y, Takeuchi O, Akira S (2008) TLR9 as a key receptor for the recognition of DNA. Adv Drug Deliv Rev 60(7):795–804. https://doi.org/10.1016/j.addr.2007.12.004CrossRefPubMed

Kumar L, Dwivedi M, Jain N et al (2023) The Female Reproductive Tract Microbiota: Friends and Foe. Life 13(6):1313. https://doi.org/10.3390/life13061313CrossRefPubMedPubMedCentral

Kwon M, Seo SS, Kim MK, Lee DO, Lim MC (2019) Compositional and Functional Differences between Microbiota and Cervical Carcinogenesis as Identified by Shotgun Metagenomic Sequencing. Cancers 11(3):309. https://doi.org/10.3390/cancers11030309CrossRefPubMedPubMedCentral

Kyrgiou M, Mitra A, Moscicki AB (2017) Does the vaginal microbiota play a role in the development of cervical cancer? Transl Res : J Lab Clin Med 179:168–182. https://doi.org/10.1016/j.trsl.2016.07.004CrossRef

Le Noci V, Bernardo G, Bianchi F, Tagliabue E, Sommariva M, Sfondrini L (2021) Toll Like Receptors as Sensors of the Tumor Microbial Dysbiosis: Implications in Cancer Progression. Front Cell Dev Biol 9:732192. https://doi.org/10.3389/fcell.2021.732192CrossRefPubMedPubMedCentral

Liu CJ, Xiao WY, Fang JF et al (2022) Genital Microbiota of Women From Six Ethnic Groups With and Without Human Papillomavirus Infection in Shangri-La, China. Front Cell Infect Microbiol 12:935068. https://doi.org/10.3389/fcimb.2022.935068CrossRefPubMedPubMedCentral

López-Filloy M, Cortez FJ, Gheit T et al (2022) Altered Vaginal Microbiota Composition Correlates With Human Papillomavirus and Mucosal Immune Responses in Women With Symptomatic Cervical Ectopy. Front Cell Infect Microbiol 12:884272. https://doi.org/10.3389/fcimb.2022.884272CrossRefPubMedPubMedCentral

Lyon LM, Doran KS, Horswill AR (2023) Staphylococcus aureus Fibronectin-Binding Proteins Contribute to Colonization of the Female Reproductive Tract. Infect Immun 91(1):e0046022. https://doi.org/10.1128/iai.00460-22CrossRefPubMed

Ma HM, Cui N, Zheng PS (2020) HOXA5 inhibits the proliferation and neoplasia of cervical cancer cells via downregulating the activity of the Wnt/β-catenin pathway and transactivating TP53. Cell Death Dis 11(6):420. https://doi.org/10.1038/s41419-020-2629-3CrossRefPubMedPubMedCentral

Mahla RS, Reddy MC, Prasad DV, Kumar H (2013) Sweeten PAMPs: Role of Sugar Complexed PAMPs in Innate Immunity and Vaccine Biology. Front Immunol 4:248. https://doi.org/10.3389/fimmu.2013.00248CrossRefPubMedPubMedCentral

Martínez-Campos C, Burguete-García AI, Madrid-Marina V (2017) Role of TLR9 in Oncogenic Virus-Produced Cancer. Viral Immunol 30(2):98–105. https://doi.org/10.1089/vim.2016.0103CrossRefPubMed

McCall KD, Muccioli M, Benencia F (2020) Toll-Like Receptors Signaling in the Tumor Microenvironment. Adv Exp Med Biol 1223:81–97. https://doi.org/10.1007/978-3-030-35582-1_5CrossRefPubMed

Menendez D, Shatz M, Azzam K, Garantziotis S, Fessler MB, Resnick MA (2011) The Toll-like receptor gene family is integrated into human DNA damage and p53 networks. PLoS Genet 7(3):e1001360. https://doi.org/10.1371/journal.pgen.1001360CrossRefPubMedPubMedCentral

Platz J, Beisswenger C, Dalpke A et al (2004) Microbial DNA induces a host defense reaction of human respiratory epithelial cells. J Immunol 173(2):1219–23. https://doi.org/10.4049/jimmunol.173.2.1219CrossRefPubMed

Shi S, Xu C, Fang X et al (2020) Expression profile of Toll-like receptors in human breast cancer. Mol Med Rep 21(2):786–794. https://doi.org/10.3892/mmr.2019.10853CrossRefPubMed

Song L, Lyu Y, Ding L et al (2020) Prevalence and Genotype Distribution of High-Risk Human Papillomavirus Infection in Women with Abnormal Cervical Cytology: A Population-Based Study in Shanxi Province, China. Cancer Manag Res 12:12583–12591. https://doi.org/10.2147/cmar.S269050CrossRefPubMedPubMedCentral

Tang K, McLeod L, Livis T et al (2022) Toll-like Receptor 9 Promotes Initiation of Gastric Tumorigenesis by Augmenting Inflammation and Cellular Proliferation. Cell Mol Gastroenterol Hepatol 14(3):567–586. https://doi.org/10.1016/j.jcmgh.2022.06.002CrossRefPubMedPubMedCentral

Yang Q, Wang Y, Wei X et al (2020) The Alterations of Vaginal Microbiome in HPV16 Infection as Identified by Shotgun Metagenomic Sequencing. Front Cell Infect Microbiol 10:286. https://doi.org/10.3389/fcimb.2020.00286CrossRefPubMedPubMedCentral

Zakikhany K, Efstratiou A (2012) Diphtheria in Europe: current problems and new challenges. Future Microbiol 7(5):595–607. https://doi.org/10.2217/fmb.12.24CrossRefPubMed

Titel: Cervicovaginal microbiota disorder combined with the change of cytosine phosphate guanine motif- toll like receptor 9 axis was associated with cervical cancerization
verfasst von: Xiao Zheng
Nan Hu
Jiamin Liu
Kailu Zhao
Huimin Li
Jiahao Wang
Mingxuan Zhang
Le Zhang
Li Song
Yuanjing Lyu
Meng Cui
Ling Ding
Jintao Wang
Publikationsdatum: 16.10.2023
Verlag: Springer Berlin Heidelberg
Erschienen in: Journal of Cancer Research and Clinical Oncology / Ausgabe 19/2023
Print ISSN: 0171-5216
Elektronische ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-023-05453-z

Springer Medizin

Cervicovaginal microbiota disorder combined with the change of cytosine phosphate guanine motif- toll like receptor 9 axis was associated with cervical cancerization