Cervical microbiome and cytokine profile at various stages of cervical cancer: A pilot study

PLoS ONE

Volumn 11, Issue 4, 2016, Pages

  Audirac Chalifour, Astride ^a   Torres Poveda, Kirvis ^a,e   Bahena Román, Margarita ^a   Téllez Sosa, Juan ^a   Martínez Barnetche, Jesús ^a   Cortina Ceballos, Bernardo ^a   López Estrada, Guillermina ^b   Delgado Romero, Karina ^c   Burguete García, Ana I ^a   Cantú, David ^d   García Carrancá, Alejandro ^d,f   Madrid Marina, Vicente Madrid Marina ^a  

^a INSTITUTO NACIONAL DE SALUD PÚBLICA   (Mexico)

^b Private Health Center for Gynecology   (Mexico)

^c Center for Women's Health   (Mexico)

^d INSTITUTO NACIONAL DE CANCEROLOGÍA   (Mexico)

^e Unidad Durango   (Mexico)

^f UNIVERSIDAD NACIONAL AUTÓNOMA DE MÉXICO   (Mexico)

Author keywords

[No Author keywords available]

Indexed keywords

CYTOKINE; GAMMA INTERFERON; INTERLEUKIN 10; INTERLEUKIN 4; INTERLEUKIN 6; TRANSFORMING GROWTH FACTOR BETA1; TUMOR NECROSIS FACTOR ALPHA; IFNG PROTEIN, HUMAN; IL10 PROTEIN, HUMAN; IL4 PROTEIN, HUMAN; IL6 PROTEIN, HUMAN; MESSENGER RNA; RNA; TGFB1 PROTEIN, HUMAN; TRANSCRIPTOME; TUMOR NECROSIS FACTOR;

ADULT; ARTICLE; BACTERIUM; CANCER STAGING; CONTROLLED STUDY; CROSS-SECTIONAL STUDY; FEMALE; FUSOBACTERIUM; GENE EXPRESSION; HISTOPATHOLOGY; HUMAN; LACTOBACILLUS; LACTOBACILLUS CRISPATUS; LACTOBACILLUS INERS; MAJOR CLINICAL STUDY; MICROBIAL DIVERSITY; MICROFLORA; NONHUMAN; PILOT STUDY; SNEATHIA; SQUAMOUS INTRAEPITHELIAL LESION OF THE CERVIX; UTERINE CERVIX; UTERINE CERVIX CANCER; UTERINE CERVIX CYTOLOGY; WART VIRUS; GENETICS; IMMUNOLOGY; MICROBIOLOGY; MIDDLE AGED; PATHOLOGY; SQUAMOUS CELL CARCINOMA; UTERINE CERVIX TUMOR;

ADULT; CARCINOMA, SQUAMOUS CELL; CROSS-SECTIONAL STUDIES; CYTOKINES; FEMALE; HUMANS; INTERFERON-GAMMA; INTERLEUKIN-10; INTERLEUKIN-4; INTERLEUKIN-6; MICROBIOTA; MIDDLE AGED; NEOPLASM STAGING; RNA, MESSENGER; RNA, NEOPLASM; SQUAMOUS INTRAEPITHELIAL LESIONS OF THE CERVIX; TRANSCRIPTOME; TRANSFORMING GROWTH FACTOR BETA1; TUMOR NECROSIS FACTOR-ALPHA; UTERINE CERVICAL NEOPLASMS;

EID: 84977490311     PISSN: None     EISSN: 19326203     Source Type: Journal    
DOI: 10.1371/journal.pone.0153274     Document Type: Article

References (86)

1. Global Burden of Disease Cancer Collaboration, Fitzmaurice C, Dicker D, Pain A, Hamavid H, Moradi-Lakeh M, et al. The GlobalBurden of Cancer2013. JAMA Oncol 2015; 1(4):505-27. doi: 10.1001/ jamaoncol.2015.0735 PMID: 26181261
2. INEGI 2012. Estadísticas de mortalidad. Cubos dinámicos y CONAPO 2012. Proyecciones de la población de México 2012-2050.
3. Munoz N, Bosch FX, de Sanjose S, Herrero R, Castellsague X, Shah KV, et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med 2003, 348:518-27. doi: 10.1056/NEJMoa021641 PMID: 12571259
4. Gillet E, Meys JF, Verstraelen H, Bosire C, De Sutter P, Temmerman M, et al. Bacterial vaginosis is associated with uterine cervical human papillomavirus infection: a meta-analysis. BMC Infect Dis 2011, 11:10. doi: 10.1186/1471-2334-11-10 PMID: 21223574
5. Guo YL, You K, Qiao J, Zhao YM, Geng L. Bacterial vaginosis is conducive to the persistence of HPV infection. Int J STD AIDS 2012; 23(8):581-4. doi: 10.1258/ijsa.2012.011342 PMID: 22930296
6. Vriend HJ, Bogaards JA, van Bergen JE, Brink AA, van den Broek IV, Hoebe CJ, et al. Incidence and persistence of carcinogenic genital human papillomavirus infections in young women with or without Chlamydia trachomatis co-infection. Cancer Med 2015 Jul 21. (Epub ahead of print)
7. Clarke MA, Rodriguez AC, Gage JC, Herrero R, Hildesheim A, Wacholder S, et al. Burk R. A large, population-based study of age-related associations between vaginal pH and human papillomavirus infection. BMC Infect Dis 2012; 12:33. doi: 10.1186/1471-2334-12-33 PMID: 22316377
8. Insinga RP, Perez G, Wheeler CM, Koutsky LA, Garland SM, Leodolter S, et al. Incident cervical HPV infections in young women: transition probabilities for CIN and infection clearance. Cancer Epidemiol Biomarkers Prev 2011; 20, 287-296. doi: 10.1158/1055-9965.EPI-10-0791 PMID: 21300618
9. Almonte M, Albero G, Molano M, Carcamo C, García PJ, Pérez G. Risk factors for human papillomavirus exposure, and co-factors for cervical cancer in Latin America and the Caribbean. Vaccine 2008;19; 26 (Suppl 11):L16-36. doi: 10.1016/j.vaccine.2008.06.008 PMID: 18945400
10. Vaccarella S, Herrero R, Dai M, Snijders PJ, Meijer CJ, Thomas JO, et al. Reproductive factors, oral contraceptive use, and human papillomavirus infection: pooled analysis of the IARC HPV prevalence surveys. Cancer Epidemiol Biomarkers Prev 2006; 15(11):2148-2153. doi: 10.1158/1055-9965.EPI-06-0556 PMID: 17119039
11. Louie KS, Castellsague X, de Sanjose S, Herrero R, Meijer CJ, Shah K, et al. Smoking and passive smoking in cervical cancer risk: pooled analysis of couples from the IARC multicentric case-control studies. Cancer Epidemiol Biomarkers Prev 2011; 20(7):1379-90. doi: 10.1158/1055-9965.EPI-11-0284 PMID: 21610224
12. Torres-Poveda K, Burguete-García AI, Cruz M, Martínez-Nava GA, Bahena-Román M, Ortíz-Flores E, et al. The SNP at -592 of human IL-10 gene is associated with serum IL-10 levels and increased risk for human papillomavirus cervical lesion development. Infect Agent Cancer 2012; 7(1):32-40. doi: 10. 1186/1750-9378-7-32 PMID: 23148667
13. Torres-Poveda K, Burguete-García AI, Bahena-Román M, Méndez-Martínez R, Zurita A, López-Estrada G, et al. Risk Allelic Load in Th2 and Th3 Cytokines gene as Biomarker of Susceptibility to cervical cancer. Submitted BMC Cancer, 2015
14. Zhang X, Zhang L, Tian C, Yang L, Wang Z. Genetic variants and risk of cervical cancer: epidemiological evidence, meta-analysis and research review. BJOG 2014; 121(6):664-73. doi: 10.1111/1471-0528.12638 Epub 2014 Feb 19. PMID: 24548744
15. Guijon F, Paraskevas M, Rand F, Heywood E, Brunham R, McNicol P. Vaginal microbial flora as a cofactor in the pathogenesis of uterine cervical intraepithelial neoplasia. Int J Gynecol Obstet 1992; 37:185-191.
16. Lehtinen M, Ault KA, Lyytikainen E, Dillner J, Garland SM, Ferris DG, et al. Chlamydia trachomatis infection and risk of cervical intraepithelial neoplasia. Sex Transm Infect 2011; 87(5):372-6. doi: 10. 1136/sti.2010.044354 PMID: 21471141
17. Sears CL, Garrett WS. Microbes, microbiota, and colon cancer. Cell Host Microbe 2014; 15(3):317-28.doi: 10.1016/j.chom.2014.02.007 PMID: 24629338
18. Dejea CM, Wick EC, Hechenbleikner EM, White JR, Mark Welch JL, Rossetti BJ, et al. Microbiota organization is a distinct feature of proximal colorectal cancers. Proc Natl Acad Sci U S A 2014; 23; 111 (51):18321-6. doi: 10.1073/pnas.1406199111 PMID: 25489084
19. Chase D, Goulder A, Zenhausern F, Monk B, Herbst-Kralovetz M. The vaginal and gastrointestinal microbiomes in gynecologic cancers: A review of applications in etiology, symptoms and treatment. Gynecol Oncol 2015; 138(1):190-200. doi: 10.1016/j.ygyno.2015.04.036 PMID: 25957158
20. Ito Y, Kishishita M, Yanase S. Induction of Epstein-Barr virus antigens in human lymphoblastoid P3HR-1 cells with culture fluid of Fusobacterium nucleatum. Cancer Res 1980; 40(11):4329-30. PMID: 6258779
21. Han YW. Fusobacterium nucleatum: a commensal-turned pathogen.CurrOpinMicrobiol2015; 23:141-7.
22. Linhares IM, Summers PR, Larsen B, Giraldo PC, Witkin SS. Contemporary perspectives on vaginal pH and lactobacilli. Am J Obstet Gynecol 2011, 204:120.e1-5.
23. Kim TK, Thomas SM, Ho M, Sharma S, Reich CI, Frank JA, et al. Heterogeneity of vaginal microbial communities within individuals. J Clin Microbiol2009; 47(4):1181-9. doi: 10.1128/JCM.00854-08 PMID: 19158255
24. Bermúdez-Morales VH, Burguete AI, Gutierrez ML, Alcocer-González JM, Madrid-Marina V. Correlation between IL-10 expression and Human Papillomavirus infection in cervical cancer. A Mechanism for Immune Response Escape. Cancer Investig 2008; 26:1037-43.
25. Alcocer-González JM, Berumen J, Tamez-Guerra R, Gariglio P, Hernández-Pando R, Bermúdez-Morales VH, et al. In Vivo Expression of Immunosuppressive Cytokines in Human Papillomavirus-Transformed Cancer Cells. Viral Immunology 2006; 19(3):481-91. PMID: 16987066
26. Giannini SL, Al-Saleh W, Piron H, Jacobs N, Doyen J, Boniver J, et al. Cytokine expression in squamous intraepithelial lesions of the uterine cervix: implications for the generation of local immunosuppression. Clin Exp Immunol. 1998; 113(2):183-9. PMID: 9717966
27. Sheu BC, Lin RH, Lien HC, Ho HN, Hsu SM, Huang SC. Predominant Th2/Tc2 polarity of tumor-infiltrating lymphocytes in human cervical cancer. J Immunol. 2001; 167(5):2972-8. PMID: 11509647
28. Spear GT, Sikaroodi M, Zariffard MR, Landay AL, French AL, Gillevet PM. Comparison of the Diversity of the Vaginal Microbiota in HIV-Infected & HIV-Uninfected women with or without Bacterial Vaginosis. Journal of Infectious Diseases 2008; 198:1131-40. doi: 10.1086/591942 PMID: 18717638
29. Huang YE, Wang Y, He Y, Ji Y, Wang LP, Sheng HF, et al. Homogeneity of the vaginal microbiome at the cervix, posterior fornix, and vaginal canal in pregnant Chinese women.MicrobEcol2015; 69(2):407-14. doi: 10.1007/s00248-014-0487-1 Epub 2014 Sep 18.
30. Behbakht K, Friedman J, Heimler I, Aroutcheva A, Simoes J, Faro S. Role of the vaginal microbiological ecosystem and cytokine profile in the promotion of cervical dysplasia: A case-control study. Infect Dis Obstet Gynecol 2002; 10:181-6. PMID: 12648311
31. Gao W, Weng J, Gao Y, Chen X. Comparison of the vaginalmicrobiota diversity of women with and without human papillomavirus infection: a cross-sectional study. BMC Infect Dis 2013; 13:271. doi: 10. 1186/1471-2334-13-271 PMID: 23758857
32. Smith BC, McAndrew T, Chen Z, Harari A, Barris DM, Viswanathan S, et al. The cervical microbiome over 7 years and a comparison of methodologies for its characterization. PLoS One 2012; 7(7):e40425. doi: 10.1371/journal.pone.0040425 Epub 2012 Jul 9. PMID: 22792313
33. Anahtar MN, Byrne EH, Doherty KE, Bowman BA, Yamamoto HS, Soumillon M et al. Cervicovaginal Bacteria Are a Major Modulator of Host Inflammatory Responses in the Female Genital Tract, Immunity 2015; 42(5):965-76. doi: 10.1016/j.immuni.2015.04.019 PMID: 25992865
34. Torres-Poveda K, Bahena-Román M, Madrid-González C, Burguete-García AI, Bermúdez-Morales VH, Peralta-Zaragoza O, et al. Role of IL-10 and TGF-β1 in local immunosuppression in HPV-associated cervical neoplasia. World J Clinical Oncology 2014; 5(4):753-63. doi: 10.5306/wjco.v5.i4.753
35. Bernard HU, Chan SY, Manos MM, Ong CK, Villa LL, Delius H, et al. Identification and assessment of known and novel human papillomaviruses by polymerase chain reaction amplification, restriction fragment length polymorphisms, nucleotide sequence, and phylogenetic algorithms. J Infect Dis 1994 70:1077-85. J Infect Dis 70:1077-85. doi: 10.1093/infdis/170.5.1077
36. Yoshikawa H, Kawana T, Kitagawa K, Mizuno M, Yoshikura H, Iwamoto A. Detection and typing of multiple genital human papillomaviruses by DNA amplification with consensus primers. Jpn J Cancer Res 1991; 82:524-31. PMID: 1648051
37. de Roda Husman AM, Walboomers JM, van den Brule AJ, Meijer CJ, Snijders PJ. The use general primers GP5 and GP6 elongated at their 3? end with adjacent highly conserved sequences improves human papillomavirus detection by PCR. J Gen Virol 1995; 76:1057-62. doi: 10.1099/0022-1317-76-4-1057 PMID: 9049358
38. Lee D-H, Hwang NR, Lim MC, Yoo CW, Joo J, Kim J-Y, et al. Comparison of the performance of Anyplex II HPV HR, the Cobas 4800 human papillomavirus test and Hybrid Capture 2. Annals of Clinical Biochemistry: An international journal of biochemistry and laboratory medicine [Internet]. 2015 Oct 20; Available from: http://acb.sagepub.com/content/early/2016/01/23/0004563215614036.abstract
39. El-Sherif AM, Seth R, Tighe PJ, Jenkins D. Quantitative analysis of IL-10 and IFN-c mRNA levels in normal cervix and human papillomavirus type 16 associated cervical precancer. J Pathol 2001; 195:179-85. doi: 10.1002/path.929 PMID: 11592096
40. Nossa CW, Oberdorf WE, Yang L, Aas JA, Paster BJ, Desantis TZ, et al. Design of 16S rRNA gene primers for 454 pyrosequencing of the human foregut microbiome. World J Gastroenterol2010; 7; 16 (33):4135-44002E. doi: 10.3748/wjg.v16.i33.4135 PMID: 20806429
41. Girke T. FASTQ Quality Plots, R; A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. URL 05-Dec-13 R Core Team. (2013)
42. Caporaso JG, Kuczynski J, Stombaugh J, Bittinger K, Bushman FD, Costello EK, et al. QIIME allows analysis of high-throughput community sequencing data. Nat Methods 2010; 7(5):335-6. doi: 10.1038/ nmeth.f.303 Epub 2010 Apr 11. PMID: 20383131
43. Caporaso JG, Bittinger K, Bushman FD, DeSantis TZ, Andersen GL, Knight R. PyNAST: a flexible tool for aligning sequences to a template alignment. Bioinformatics 2010; 26:266-67. doi: 10.1093/ bioinformatics/btp636 PMID: 19914921
44. Edgar R. C. Search and clustering orders of magnitude faster than BLAST. Bioinformatics 2010; 26 (19), 2460-61. doi: 10.1093/bioinformatics/btq461 Epub 2010 Aug 12 PMID: 20709691
45. De Santis TZ, Hugenholtz P, Larsen N, Rojas M, Brodie EL, Keller K, et al. Greengenes, a chimerachecked 16S rRNA gene database and workbench compatible with ARB. Appl Environ Microb 2006; 72(7): 5069-72. doi: 10.1128/AEM.03006-05
46. Lozupone C, Knight R. UniFrac: A New Phylogenetic Method for Comparing Microbial Communities. Appl Environ Microbiol2005; 71(12): 8228-35. doi: 10.1128/AEM.71.12.8228-8235.2005 PMID: 16332807
47. Vazquez-Baeza Y, Pirrung M, Gonzalez A, Knight R. Emperor: A tool for visualizing high-throughput microbial community data. Gigascience 2013; 2(1):16. doi: 10.1186/2047-217X-2-16 PMID: 24280061
48. Gajer P, Brotman RM, Bai G, Sakamoto J, Schutte UM, Zhong X, et al. Temporal dynamics of the human vaginal microbiota. Sci Transl Med 2012; 4:132ra152. doi: 10.1126/scitranslmed.3003605
49. Shew ML, Ermel AC, Weaver BA, Tong Y, Tu W, Kester LM, et al. Association of Chlamydia trachomatis infection with redetection of human papillomavirus after apparent clearance. J Infect Dis 2013; 208 (9): 1416-21. doi: 10.1093/infdis/jit346 PMID: 23911713
50. Ravel J, Gajer P, Abdo Z, Schneider GM, Koenig SSK, McCulle SL, et al. Vaginal microbiome of reproductive-age women. Proc Natl Acad Sci U S A 2011; 108 (Suppl. 1): 4680-87. doi: 10.1073/pnas.1002611107 Epub 2010 Jun 3. PMID: 20534435
51. van de Wijgert JH, Borgdorff H, Verhelst R, Crucitti T, Francis S, Verstraelen H, et al. The vaginal microbiota: what have we learned after a decade of molecular characterization? PLoS One 2014; 9(8): e105998. doi: 10.1371/journal.pone.0105998. eCollection 2014 PMID: 25148517
52. Borgdorff H, Tsivtsivadze E, Verhelst R, Marzorati M, Jurriaans S, Ndayisaba GF, et al. Lactobacillusdominated cervicovaginal microbiota associated with reduced HIV/STI prevalence and genital HIV viral load in African women.ISME J 2014; 8(9):1781-93. doi: 10.1038/ismej.2014.26 Epub 2014 Mar 6.PMID: 24599071
53. Dols JA, Reid G, Kort R, Schuren FH, Tempelman H, Bontekoe TR, et al. PCR-based identification of eight Lactobacillus species and 18hr-HPVgenotypes in fixed cervical samples of South African women at risk of HIV and BV. DiagnCytopathol2012; 40(6):472-7. doi: 10.1002/dc.21786 Epub 2011 Oct 24.
54. Lee JE, Lee S, Lee H, Song YM, Lee K, Han MJ, et al. Association of the Vaginal Microbiota with Human Papillomavirus Infection in a Korean Twin Cohort. PLoS One 2013; 8(5): e63514. doi: 10.1371/ journal.pone.0063514. Print 2013 PMID: 23717441
55. Harwich MD Jr, Serrano MG, Fettweis JM, Alves JM, Reimers MA; Vaginal Microbiome Consortium (additional members), et al. Genomic sequence analysis and characterization of Sneathia amnii sp. nov.BMC Genomics 2012; 13Suppl 8:S4. doi: 10.1186/1471-2164-13-S8-S4 Epub 2012 Dec 17.PMID: 23281612
56. Nawrot R, Kamieniarz K, Malinowska M, Jozefiak A, Kedzia W, Kwasniewska A, et al. The prevalence of Leptotrichia amnionii in cervical swabs of HPV positive and negative women. Eur J Gynaecol Oncol 2010; 31(4):425-28. PMID: 20882886
57. Shipitsyna E, Roos A, Datcu R, Hallén A, Fredlund H, Jensen JS, et al. Composition of the vaginal microbiota in women of reproductive age-sensitive and specific molecular diagnosis of bacterial vaginosis is possible? PLoS One 2013; 8(4):e60670. doi: 10.1371/journal.pone.0060670. Print 2013 PMID: 23585843
58. Caixeta RC, Ribeiro AA, Segatti KD, Saddi VA, Figueiredo Alves RR, Dos Santos Carneiro MA, et al. Association between the human papillomavirus, bacterial vaginosis and cervicitis and the detection ofabnormalities in cervical smears from teenage girls and young women. DiagnCytopathol2015 Jul 14. doi: 10.1002/dc.23301
59. Shah NB, Suri RM, Melduni RM, Patel R, Kommedal O, Saebø O, et al. Shuttleworthia satelles endocarditis: evidence of non-dental human disease. J Infect 2010; 60(6):491-3. doi: 10.1016/j.jinf.2010.02.008 Epub 2010 Feb 17. PMID: 20170673
60. Oh HY, Kim BS, Seo SS, Kong JS, Lee JK, Park SY, et al. The association of uterine cervical microbiota with an increased risk for cervical intraepithelial neoplasia in Korea. Clin Microbiol Infect 2015; 21 (7):674.e1-9. doi: 10.1016/j.cmi.2015.02.026 Epub 2015 Mar 6.
61. Sagata N, Haake SK, Mannon P, Lemon KP, Waldron L, Gevers D, et al. Composition of the adult digestive tract bacterial microbiome based in seven mouth surfaces tonsil, throat and stool samples. Genome Biol 2012; 13(6):R42. doi: 10.1186/gb-2012-13-6-r42 PMID: 22698087
62. Signat B, Roques C, Poulet P, Duffaut D. Fusobacterium nucleatum in periodontal health and disease. Curr Issues MolBiol2011; 13(2):25-36.
63. Kostic AD, Gevers D, Pedamallu CS, Michaud M, Duke F, Earl AM, et al. Genomic analysis identifies association of Fusobacterium with colorectal carcinoma. Genome Res 2012; 22(2):292-8. doi: 10. 1101/gr.126573.111 Epub 2011 Oct 18. PMID: 22009990
64. Castellarin M, Warren RL, Freeman JD, Dreolini L, Krzywinski M, Strauss J, et al. Fusobacterium nucleatum infection is prevalent in human colorectal carcinoma. Genome Res 2012; 22(2):299-306. doi: 10. 1101/gr.126516.111 Epub 2011 Oct 18. PMID: 22009989
65. Ahn J, Sinha R, Pei Z, Dominianni C, Wu J, Shi J, et al. Human gut microbiome and risk for colorectal cancer. J Natl Cancer Inst 2013; 105(24):1907-11. doi: 10.1093/jnci/djt300 Epub 2013 Dec 6. PMID: 24316595
66. Tahara T, Yamamoto E, Suzuki H, Maruyama R, Chung W, Garriga J, et al. Fusobacterium in colonic flora and molecular features of colorectal carcinoma.Cancer Res 2014; 74(5):1311-8. doi: 10.1158/ 0008-5472.CAN-13-1865 Epub 2014 Jan 2. PMID: 24385213
67. Burns MB, Lynch J, Starr TK, Knights D, Blekhman R. Virulence genes are a signature of the microbiome in the colorectal tumor microenvironment. Genome Med 2015; 7(1):55. doi: 10.1186/s13073-015-0177-8 eCollection 2015. PMID: 26170900
68. Rubinstein MR, Wang X, Liu W, Hao Y, Cai G, Han YW. Fusobacterium nucleatum promotes colorectal carcinogenesis by modulating E-cadherin/β-catenin signaling via its FadA adhesin. Cell Host Microbe 2013; 14(2):195-206. doi: 10.1016/j.chom.2013.07.012 PMID: 23954158
69. Kostic AD, Chun E, Robertson L, Glickman JN, Gallini CA, Michaud M, et al. Fusobacterium nucleatum potentiates intestinal tumorigenesis and modulates the tumor-immune microenvironment. Cell Host Microbe 2013; 14(2):207-15. doi: 10.1016/j.chom.2013.07.007 PMID: 23954159
70. Rodríguez-Sastre MA, González-Maya L, Delgado R, Lizano M, Tsubaki G, Mohar A, et al. Abnormal distribution of E-cadherin and beta-catenin in different histologic types of cancer of the uterine cervix. Gynecol Oncol 2005; 97(2):330-6. PMID: 15863126
71. Branca M, Giorgi C, Ciotti M, Santini D, Di Bonito L, Costa S, et al. Down-regulation of E-cadherin is closely associated with progression of cervical intraepithelial neoplasia (CIN), but not with high-risk human papillomavirus (HPV) or disease outcome in cervical cancer. Eur J Gynaecol Oncol 2006; 27 (3):215-23. PMID: 16800245
72. Auvinen E, Carpen O, Korpela T, Ronty M, Vaheri A, Tarkkanen J. Altered expression of ezrin, E-Cadherin and β-Catenin in cervical neoplasia. Neoplasma 2013; 60(1):56-61. doi: 10.4149/neo-2013-008PMID: 23067217
73. Velsko IM, Chukkapalli SS, Rivera-Kweh MF, Chen H, Zheng D, Bhattacharyya I, et al. Fusobacterium nucleatum Alters Atherosclerosis Risk Factors and Enhances Inflammatory Markers with an Atheroprotective Immune Response in ApoEnull Mice. PLoS One 2015; 10(6):e0129795. doi: 10.1371/journal. pone.0129795. eCollection 2015 PMID: 26079509
74. Ohnmacht C, Park JH, Cording S, Wing JB, Atarashi K, Obata Y, et al. The microbiota regulates type 2 immunity through RORaγt+ T cells. Science 2015 Jul 9. pii: aac4263.
75. Feng Q, Wei H, Morihara J, Stern J, Yu M, Kiviat N, et al. Th2 type inflammation promotes the gradual progression of HPV-infected cervical cells to cervical carcinoma. Gynecol Oncol 2012; 127(2):412-9.doi: 10.1016/j.ygyno.2012.07.098 PMID: 22828962
76. Chen ZF, Xu Q, Ding JB, Zhang Y, Du R, Ding Y. CD4+CD25+Foxp3+ Treg and TGF-beta play important roles in pathogenesis of Uygur cervical carcinoma.Eur J Gynaecol Oncol 2012; 33(5):502-7.PMID: 23185797
77. Punt S, van Vliet ME, Spaans VM, de Kroon CD, Fleuren GJ, Gorter A, et al. FoxP3(+) and IL-17(+) cells are correlated with improved prognosis in cervical adenocarcinoma. Cancer Immunol Immunother 2015; 64(6):745-53. doi: 10.1007/s00262-015-1678-4 PMID: 25795131
78. Gagliani N, Vesely MC, Iseppon A, Brockmann L, Xu H, Palm NW, et al. Th17 cells transdifferentiate into regulatory T cells during resolution of inflammation. Nature 2015; 523(7559):221-5. doi: 10.1038/ nature14452 Epub 2015 Apr 29. PMID: 25924064
79. Prata TT, Bonin CM, Ferreira AM, Padovani CT, Fernandes CE, Machado AP, et al. Local immunosuppression induced by high viral load of human papillomavirus: characterization of cellular phenotypes producing interleukin-10 in cervical neoplastic lesions. Immunology 2015 Jun 8. doi: 10.1111/imm. 12487
80. Bermúdez-Morales VH, Peralta-Zaragoza O, Moreno J, Alcocer-González JM, Madrid-Marina V. IL-10 expression is regulated by HPV E2 protein in cervical cancer cells. Molecular Medicine Reports 2011; 4 (2):369-75. doi: http://dx.doi.org/10.3892/mmr.2011.429 PMID: 21468579
81. Peralta-Zaragoza O, Bermúdez-Morales V, Gutiérrez-Xicotencatl L, Alcocer-González J, Recillas-Targa F, Madrid-Marina V. Human papilomavirus-16 E6 and E7 proteins induce activation of human TGF-1 basal promoter in epithelial cells throughout a Sp1 recognition sequence. Viral Immunology 2006; 19(3):468-80.
82. Shondel SM, Helm CW, Gercel-Taylor C, Taylor DD. Differential expression of T-cell CD3-zeta chains in patients with cervical dysplasia before and after treatment. Int. J. Gynecol. Cancer.2007; 17 (6):1278-82. PMID: 17997796
83. Hu T, Yang P, Zhu H, Chen X, Xie X, Yang M, et al. Accumulation of invariant NKT cells with increased IFN-γ production in persistent high-risk HPV-infected high-grade cervical intraepithelial neoplasia. DiagnPathol2015; 10:20.
84. Gosmann C, Frazer IH, Mattarollo SR, Blumenthal A. IL-18, but not IL-12, induces production of IFN-γ in the immunosuppressive environment of HPV16 E7 transgenic hyperplastic skin. J Invest Dermatol 2014; 134(10):2562-9. doi: 10.1038/jid.2014.201 PMID: 24756108
85. Marangon AV, Guelsin GA, Visentainer JE, Borelli SD, Watanabe MA, Consolaro ME, et al. The association of the immune response genes to human papillomavirus-related cervical disease in a Brazilian population. Biomed Res Int2013; 2013:146079. doi: 10.1155/2013/146079 PMID: 23936772
86. Yang W, Song Y, Lu YL, Sun JZ, Wang HW.Increased expression of programmed death (PD)-1 and its ligand PD-L1 correlates with impaired cell-mediated immunity in high-risk human papillomavirusrelated cervical intraepithelial neoplasia. Immunology 2013; 139(4):513-22. doi: 10.1111/imm.12101PMID: 23521696