Aerobic vaginitis is associated with carbonic anhydrase IX in cervical intraepithelial neoplasia.
Aerobic vaginitis
CAIX enzyme
Carbonic anhydrase 9
Cervical intraepithelial neoplasia
Microbiota alteration
Uterine cervix dysplasia
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
16 Apr 2024
16 Apr 2024
Historique:
received:
05
09
2023
accepted:
18
03
2024
medline:
17
4
2024
pubmed:
17
4
2024
entrez:
16
4
2024
Statut:
epublish
Résumé
The aim of this study was to analyze the association between vaginal microbiota, carbonic anhydrase IX (CAIX) and histological findings of cervical intraepithelial neoplasia (CIN). The study included 132 females, among them 66 were diagnosed with high-grade intraepithelial lesion (CIN2, CIN3, and cancer), 14 with low-grade disease, and 52 assigned to the control group. An interview focused on the behavior risk factors, together with vaginal fluid pH measurement, wet mount microscopy, detection of Chlamydia trachomatis, and Trichomonas vaginalis were performed. After colposcopy, high-grade abnormalities were detected via direct biopsies and treated with conization procedure. Conuses were immuno-stained with CAIX antibody. The histological findings were CIN1 (n = 14), and CIN2+ (included CIN2 (n = 10), CIN3 (n = 49), and cancer (n = 7; squamous cell carcinomas)). Prevalence of bacterial vaginosis (BV) was similar between the groups. Moderate or severe aerobic vaginitis (msAV) was diagnosed more often among CIN2+ (53.0%) than CIN1 (21.4%). Moderate or strong immunostaining of CAIX (msCAIX) was not detected among CIN1 cases. Thus, msAV was prevalent in CAIX non-stained group (p = 0.049) among CIN2 patients. Co-location of msAV and msCAIX was found in CIN3. Regression model revealed that msAV associated with high-grade cervical intraepithelial neoplasia independently from smoking and the number of partners.
Identifiants
pubmed: 38627429
doi: 10.1038/s41598-024-57427-x
pii: 10.1038/s41598-024-57427-x
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
8789Subventions
Organisme : Lietuvos Mokslo Taryba
ID : S-SEN-20-10
Informations de copyright
© 2024. The Author(s).
Références
Koshiol, J. et al. Persistent human papillomavirus infection and cervical neoplasia: A systematic review and meta-analysis. Am. J. Epidemiol. 168, 123–137 (2008).
pubmed: 18483125
pmcid: 2878094
doi: 10.1093/aje/kwn036
Colombo, N. et al. Pembrolizumab for persistent, recurrent, or metastatic cervical cancer. N. Engl. J. Med. 385, 1856–1867. https://doi.org/10.1056/NEJMoa2112435 (2021).
doi: 10.1056/NEJMoa2112435
pubmed: 34534429
Dillner, J., Elfström, K. M. & Baussano, I. Prospects for accelerated elimination of cervical cancer. Prev. Med. 153, 106827 (2021).
pubmed: 34599922
doi: 10.1016/j.ypmed.2021.106827
Shu, Y. et al. Immunogenicity and safety of two novel human papillomavirus 4- and 9-valent vaccines in Chinese women aged 20–45 years: A randomized, blinded, controlled with Gardasil (type 6/11/16/18), phase III non-inferiority clinical trial. Vaccine 40, 6947–6955 (2022).
pubmed: 36283897
doi: 10.1016/j.vaccine.2022.10.022
McBride, A. A. & Warburton, A. The role of integration in oncogenic progression of HPV-associated cancers. PLoS Pathog. 13, e1006211 (2017).
pubmed: 28384274
pmcid: 5383336
doi: 10.1371/journal.ppat.1006211
Williams, V. M., Filippova, M., Soto, U. & Duerksen-Hughes, P. J. HPV-DNA integration and carcinogenesis: Putative roles for inflammation and oxidative stress. Future Virol. 6, 45–57 (2011).
pubmed: 21318095
pmcid: 3037184
doi: 10.2217/fvl.10.73
Valasoulis, G. et al. Cervical HPV infections, sexually transmitted bacterial pathogens and cytology findings—A molecular epidemiology study. Pathogens 12, 1347 (2023).
pubmed: 38003814
pmcid: 10675441
doi: 10.3390/pathogens12111347
Yamaguchi, M. et al. Risk factors for HPV infection and high-grade cervical disease in sexually active Japanese women. Sci. Rep. 11, 2898 (2021).
pubmed: 33536516
pmcid: 7858628
doi: 10.1038/s41598-021-82354-6
Wagner, M., Jasek, M. & Karabon, L. Immune checkpoint molecules—Inherited variations as markers for cancer risk. Front. Immunol. 11, 721. https://doi.org/10.3389/fimmu.2020.606721 (2021).
doi: 10.3389/fimmu.2020.606721
Huang, B., Fettweis, J. M., Brooks, J. P., Jefferson, K. K. & Buck, G. A. The changing landscape of the vaginal microbiome. Clin. Lab. Med. 34, 747–761 (2014).
pubmed: 25439274
pmcid: 4254509
doi: 10.1016/j.cll.2014.08.006
Gillet, E. et al. Association between bacterial vaginosis and cervical intraepithelial neoplasia: Systematic review and meta-analysis. PLoS ONE 7, e45201 (2012).
pubmed: 23056195
pmcid: 3462776
doi: 10.1371/journal.pone.0045201
Plisko, O. et al. Aerobic vaginitis—Underestimated risk factor for cervical intraepithelial neoplasia. Diagnostics 11, 97 (2021).
pubmed: 33435407
pmcid: 7827831
doi: 10.3390/diagnostics11010097
Vieira-Baptista, P. et al. Bacterial vaginosis, aerobic vaginitis, vaginal inflammation and major Pap smear abnormalities. Eur. J. Clin. Microbiol. Infect. Dis. 35, 657–664. https://doi.org/10.1007/s10096-016-2584-1 (2016).
doi: 10.1007/s10096-016-2584-1
pubmed: 26810061
Donders, G. G. G. et al. Definition of a type of abnormal vaginal flora that is distinct from bacterial vaginosis: Aerobic vaginitis. BJOG 109, 34–43 (2002).
pubmed: 11845812
doi: 10.1111/j.1471-0528.2002.00432.x
Donders, G., Bellen, G. & Rezeberga, D. Aerobic vaginitis in pregnancy. BJOG Int. J. Obstetr. Gynaecol. 118, 1163–1170. https://doi.org/10.1111/j.1471-0528.2011.03020.x (2011).
doi: 10.1111/j.1471-0528.2011.03020.x
Hsin, M.-C. et al. Carbonic anhydrase IX promotes human cervical cancer cell motility by regulating PFKFB4 expression. Cancers 13, 1174 (2021).
pubmed: 33803236
pmcid: 7967120
doi: 10.3390/cancers13051174
Chen, Z. et al. Differential expression and function of CAIX and CAXII in breast cancer: A comparison between tumorgraft models and cells. PLoS ONE 13, e0199476 (2018).
pubmed: 29965974
pmcid: 6028082
doi: 10.1371/journal.pone.0199476
Huang, W.-J. et al. Expression of hypoxic marker carbonic anhydrase IX predicts poor prognosis in resectable hepatocellular carcinoma. PLoS ONE 10, e0119181. https://doi.org/10.1371/journal.pone.0119181 (2015).
doi: 10.1371/journal.pone.0119181
pubmed: 25738958
pmcid: 4349857
Liao, S.-Y. et al. Prognostic relevance of carbonic anhydrase-IX in high-risk, early-stage cervical cancer: A Gynecologic Oncology Group study. Gynecol. Oncol. 116, 452–458 (2010).
pubmed: 19913895
doi: 10.1016/j.ygyno.2009.10.062
Zhou, G. X., Ireland, J., Rayman, P., Finke, J. & Zhou, M. Quantification of carbonic anhydrase IX expression in serum and tissue of renal cell carcinoma patients using enzyme-linked immunosorbent assay: Prognostic and diagnostic potentials. Urology 75, 257–261 (2010).
pubmed: 19963243
doi: 10.1016/j.urology.2009.09.052
İlie, M. et al. High levels of carbonic anhydrase IX in tumour tissue and plasma are biomarkers of poor prognostic in patients with non-small cell lung cancer. Br. J. Cancer 102, 1627–1635 (2010).
pubmed: 20461082
pmcid: 2883156
doi: 10.1038/sj.bjc.6605690
Finkelmeier, F. et al. Circulating hypoxia marker carbonic anhydrase IX (CA9) in patients with hepatocellular carcinoma and patients with cirrhosis. PLoS ONE 13, e0200855. https://doi.org/10.1371/journal.pone.0200855 (2018).
doi: 10.1371/journal.pone.0200855
pubmed: 30011326
pmcid: 6047828
Luong-Player, A., Liu, H., Wang, H. L. & Lin, F. Immunohistochemical reevaluation of carbonic anhydrase IX (CA IX) expression in tumors and normal tissues. Am. J. Clin. Pathol. 141, 219–225 (2014).
pubmed: 24436269
doi: 10.1309/AJCPVJDS28KNYZLD
Woelber, L. et al. Carbonic anhydrase IX in tumor tissue and sera of patients with primary cervical cancer. BMC Cancer 11, 12. https://doi.org/10.1186/1471-2407-11-12 (2011).
doi: 10.1186/1471-2407-11-12
pubmed: 21223596
pmcid: 3027191
Liao, S.-Y. & Stanbridge E. J. Diagnostic Method Using Expression of MN/CA9 Protein in ASCUS Pap Smears. https://patents.google.com/patent/US6403327B1/en (Accessed 29 December 2020) (2002).
CA-IX, p16, Proliferative Markers, and HPV in Diagnosing Cervical Lesions in Patients with Abnormal Cervical Cells—Full Text View—ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT00892866 (Accessed 10 December 2020).
Drenckhan, A. et al. CAIX furthers tumour progression in the hypoxic tumour microenvironment of esophageal carcinoma and is a possible therapeutic target. J. Enzyme Inhib. Med. Chem. 33, 1024–1033. https://doi.org/10.1080/14756366.2018.1475369 (2018).
doi: 10.1080/14756366.2018.1475369
pubmed: 29865880
pmcid: 6010094
Triner, D. & Shah, Y. M. Hypoxia-inducible factors: A central link between inflammation and cancer. J. Clin. Investig. 126, 3689–3698 (2016).
pubmed: 27525434
pmcid: 5096825
doi: 10.1172/JCI84430
Ward, C. et al. Carbonic anhydrase IX (CAIX), cancer, and radiation responsiveness. Metabolites 8, 13 (2018).
pubmed: 29439394
pmcid: 5874614
doi: 10.3390/metabo8010013
Jeong, S. Y. et al. Validation of potential protein markers predicting chemoradioresistance in early cervical cancer by immunohistochemistry. Front. Oncol. 11, 665595 (2021).
pubmed: 34350111
pmcid: 8327183
doi: 10.3389/fonc.2021.665595
Chen, X.-J. et al. The role of the hypoxia-Nrp-1 axis in the activation of M2-like tumor-associated macrophages in the tumor microenvironment of cervical cancer. Mol. Carcinog. 58, 388–397 (2019).
pubmed: 30362630
doi: 10.1002/mc.22936
Tupá, V., Drahošová, S., Grendár, M. & Adamkov, M. Expression and association of carbonic anhydrase IX and cyclooxygenase-2 in colorectal cancer. Pathol. Res. Pract. 215, 705 (2019).
pubmed: 30638861
doi: 10.1016/j.prp.2019.01.012
Kong, C. S. et al. The relationship between human papillomavirus status and other molecular prognostic markers in head and neck squamous cell carcinomas. Int. J. Radiat. Oncol. Biol. Phys. 74, 553–561 (2009).
pubmed: 19427557
pmcid: 2768774
doi: 10.1016/j.ijrobp.2009.02.015
Temiz, E. et al. Inhibition of carbonic anhydrase IX promotes apoptosis through intracellular pH level alterations in cervical cancer cells. Int. J. Mol. Sci. 22, 6098 (2021).
pubmed: 34198834
pmcid: 8201173
doi: 10.3390/ijms22116098
Monti, M. et al. Relationship between cervical excisional treatment for cervical intraepithelial neoplasia and obstetrical outcome. Minerva Obstet. Gynecol. 73, 233–246 (2021).
pubmed: 33140628
doi: 10.23736/S2724-606X.20.04678-X
Bogani, G. et al. Development of a nomogram predicting the risk of persistence/recurrence of cervical dysplasia. Vaccines 10, 579 (2022).
pubmed: 35455328
pmcid: 9029732
doi: 10.3390/vaccines10040579
Loopik, D. L., Doucette, S., Bekkers, R. L. M. & Bentley, J. R. Regression and progression predictors of CIN2 in women younger than 25 years. J. Lower Genital Tract Dis. 20, 213–217 (2016).
doi: 10.1097/LGT.0000000000000215
Moscicki, A.-B. et al. Rate of and risks for regression of CIN-2 in adolescents and young women. Obstet. Gynecol. 116, 1373–1380 (2010).
pubmed: 21099605
pmcid: 3057366
doi: 10.1097/AOG.0b013e3181fe777f
Mitra, A. et al. The vaginal microbiota associates with the regression of untreated cervical intraepithelial neoplasia 2 lesions. Nat. Commun. 11, 1999 (2020).
pubmed: 32332850
pmcid: 7181700
doi: 10.1038/s41467-020-15856-y
Kim, J.-Y. et al. Tumor-associated carbonic anhydrases are linked to metastases in primary cervical cancer. J. Cancer Res. Clin. Oncol. 132, 302–308 (2006).
pubmed: 16416108
doi: 10.1007/s00432-005-0068-2
Moscicki, A.-B., Shi, B., Huang, H., Barnard, E. & Li, H. Cervical-vaginal microbiome and associated cytokine profiles in a prospective study of HPV 16 acquisition, persistence, and clearance. Front. Cell Infect. Microbiol. 10, 569022 (2020).
pubmed: 33102255
pmcid: 7546785
doi: 10.3389/fcimb.2020.569022
Ranganathan, P. & Aggarwal, R. Study designs: Part 1—An overview and classification. Perspect. Clin. Res. 9, 184–186 (2018).
pubmed: 30319950
pmcid: 6176693
doi: 10.4103/picr.PICR_124_18
Conn, V. S., Ruppar, T. M., Phillips, L. J. & Chase, J.-A.D. Using meta-analyses for comparative effectiveness research. Nurs. Outlook 60, 182–190 (2012).
pubmed: 22789450
pmcid: 3396882
doi: 10.1016/j.outlook.2012.04.004
Donders, G. G. G. et al. Comparison of two types of dipsticks to measure vaginal pH in clinical practice. Eur. J. Obstet. Gynecol. Reprod. Biol. 134, 220–224 (2007).
pubmed: 16952417
doi: 10.1016/j.ejogrb.2006.07.016
Donders, G. G. G. et al. Variability in diagnosis of clue cells, lactobacillary grading and white blood cells in vaginal wet smears with conventional bright light and phase contrast microscopy. Eur. J. Obstet. Gynecol. Reprod. Biol. 145, 109–112 (2009).
pubmed: 19481329
doi: 10.1016/j.ejogrb.2009.04.012
Donders, G. G. G. Definition and classification of abnormal vaginal flora. Best Pract. Res. Clin. Obstetr. Gynaecol. 21, 355–373 (2007).
doi: 10.1016/j.bpobgyn.2007.01.002
Donders, G. G. G. Definition and classification of abnormal vaginal flora. Best Pract. Res. Clin. Obstet. Gynaecol. 21, 355–373 (2007).
pubmed: 17434799
doi: 10.1016/j.bpobgyn.2007.01.002
Donders, G. G. Microscopy of the bacterial flora on fresh vaginal smears. Infect. Dis. Obstet. Gynecol. 7, 177–179 (1999).
pubmed: 10449264
pmcid: 1784739
Donders, G. G., Vereecken, A., Salembier, G., Van Bulck, B. & Spitz, B. Assessment of vaginal lactobacillary flora in wet mount and fresh or delayed gram’s stain. Infect. Dis. Obstet. Gynecol. 4, 2–6 (1996).
pubmed: 18476056
pmcid: 2364465
doi: 10.1002/(SICI)1098-0997(1996)4:1<2::AID-IDOG2>3.0.CO;2-5
Sellors, J. W. et al. Colposcopy and Treatment of Cervical Intraepithelial Neoplasia: A Beginner’s Manual (International Agency for Research on Cancer, 2003).
Waxman, A. G., Chelmow, D., Darragh, T. M., Lawson, H. & Moscicki, A.-B. Revised terminology for cervical histopathology and its implications for management of high-grade squamous intraepithelial lesions of the cervix. Obstet. Gynecol. 120, 1465–1471 (2012).
pubmed: 23168774
pmcid: 4054813
doi: 10.1097/AOG.0b013e31827001d5
Stravinskiene, D. et al. New monoclonal antibodies for a selective detection of membrane-associated and soluble forms of carbonic anhydrase IX in human cell lines and biological samples. Biomolecules 9, 304 (2019).
pubmed: 31349673
pmcid: 6723738
doi: 10.3390/biom9080304
Simanaviciene, V. et al. Studies on the prevalence of oncogenic HPV types among Lithuanian women with cervical pathology. J. Med. Virol. 87, 461–471 (2015).
pubmed: 25196501
doi: 10.1002/jmv.24073
Grincevičienė, Š et al. Factors, associated with elevated concentration of soluble carbonic anhydrase IX in plasma of women with cervical dysplasia. Sci. Rep. 12, 15397 (2022).
pubmed: 36100684
pmcid: 9470728
doi: 10.1038/s41598-022-19492-y
Crum, C. P. et al. Dynamics of human papillomavirus infection between biopsy and excision of cervical intraepithelial neoplasia: Results from the ZYC101a protocol. J. Infect. Dis. 189, 1348–1354 (2004).
pubmed: 15073670
doi: 10.1086/382956
de Vet, H. C. & Sturmans, F. Risk factors for cervical dysplasia: Implications for prevention. Public Health 108, 241–249 (1994).
pubmed: 8066168
doi: 10.1016/S0033-3506(94)80002-2
Tasic, D. et al. The impact of environmental and behavioural cofactors on the development of cervical disorders in HR-HPV-infected women in Serbia. Epidemiol. Infect. 146, 1714–1723 (2018).
pubmed: 29923470
pmcid: 9507945
doi: 10.1017/S0950268818001668
Collins, S., Rollason, T. P., Young, L. S. & Woodman, C. B. J. Cigarette smoking is an independent risk factor for cervical intraepithelial neoplasia in young women: A longitudinal study. Eur. J. Cancer 46, 405–411 (2010).
pubmed: 19819687
pmcid: 2808403
doi: 10.1016/j.ejca.2009.09.015
Becker, T. M. et al. Sexually transmitted diseases and other risk factors for cervical dysplasia among southwestern Hispanic and non-Hispanic white women. JAMA 271, 1181–1188 (1994).
pubmed: 8151876
doi: 10.1001/jama.1994.03510390051029
Łaniewski, P. et al. Linking cervicovaginal immune signatures, HPV and microbiota composition in cervical carcinogenesis in non-Hispanic and Hispanic women. Sci. Rep. 8, 7593 (2018).
pubmed: 29765068
pmcid: 5954126
doi: 10.1038/s41598-018-25879-7
Jahic, M., Mulavdic, M., Hadzimehmedovic, A. & Jahic, E. Association between aerobic vaginitis, bacterial vaginosis and squamous intraepithelial lesion of low grade. Med. Arch. 67, 94–96 (2013).
pubmed: 24341052
doi: 10.5455/medarh.2013.67.94-96
Boccardo, E., Lepique, A. P. & Villa, L. L. The role of inflammation in HPV carcinogenesis. Carcinogenesis 31, 1905–1912 (2010).
pubmed: 20819779
doi: 10.1093/carcin/bgq176
Iwata, T. et al. Cytokine profile in cervical mucosa of Japanese patients with cervical intraepithelial neoplasia. Int. J. Clin. Oncol. 20, 126–133 (2015).
pubmed: 24578180
doi: 10.1007/s10147-014-0680-8
Kemp, T. J. et al. Elevated systemic levels of inflammatory cytokines in older women with persistent cervical human papillomavirus infection. Cancer Epidemiol. Biomark. Prev. 19, 1954–1959 (2010).
doi: 10.1158/1055-9965.EPI-10-0184
Läsche, M., Urban, H., Gallwas, J. & Gründker, C. HPV and other microbiota; who’s good and who’s bad: Effects of the microbial environment on the development of cervical cancer—A non-systematic review. Cells 10, 714 (2021).
pubmed: 33807087
pmcid: 8005086
doi: 10.3390/cells10030714
Maarsingh, J. D., Łaniewski, P. & Herbst-Kralovetz, M. M. Immunometabolic and potential tumor-promoting changes in 3D cervical cell models infected with bacterial vaginosis-associated bacteria. Commun. Biol. 5, 1–13 (2022).
doi: 10.1038/s42003-022-03681-6
Mitchell, C. & Marrazzo, J. Bacterial vaginosis and the cervicovaginal immune response. Am. J. Reprod. Immunol. 71, 555–563 (2014).
pubmed: 24832618
pmcid: 4128638
doi: 10.1111/aji.12264
Knorr, S. et al. Widespread bacterial lysine degradation proceeding via glutarate and L-2-hydroxyglutarate. Nat. Commun. 9, 5071 (2018).
pubmed: 30498244
pmcid: 6265302
doi: 10.1038/s41467-018-07563-6
Valasoulis, G. et al. The influence of sexual behavior and demographic characteristics in the expression of HPV-related biomarkers in a colposcopy population of reproductive age greek women. Biology 10, 713 (2021).
pubmed: 34439947
pmcid: 8389230
doi: 10.3390/biology10080713