DOI QR코드

DOI QR Code

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

  • Hao, Yi (The Affiliated Tumor Hospital of Xinjiang Medical University) ;
  • Yuan, Jian-Ling (The Affiliated Tumor Hospital of Xinjiang Medical University) ;
  • Abudula, Abulizi (Xinjiang Key Laboratory of Molecular Biology and Endemic Diseases, Xinjiang Medical University) ;
  • Hasimu, Axiangu (Department of Pathology, Xinjiang Medical University) ;
  • Kadeer, Nafeisha (Xinjiang Key Laboratory of Molecular Biology and Endemic Diseases, Xinjiang Medical University) ;
  • Guo, Xia (Xinjiang Key Laboratory of Molecular Biology and Endemic Diseases, Xinjiang Medical University)
  • 발행 : 2014.07.30

초록

Background: Cervical cancer is listed as one of high-incidence endemic diseases in Xinjiang. Our study aimed to evaluate the expression of TLR9 in uterine cervical tissues of Uyghur women and examine associations with clinicopathological variables. We further characterized the direct effects of TLR9 upon the selective silencing of human papillomavirus (HPV) E6 and E7 oncoprotein expression in HPV 16-positive human cervical carcinoma cells treated with siRNA in vitro. Materials and Methods: Immunohistochemistry was applied to evaluate TLR9 expression in 97 formalin-fixed paraffin-embedded cervical samples from Uyghur women; 32 diagnosed with cervical squamous cell carcinomas (CSCC), 14 with low-grade cervical intraepithelial neoplasias (CINI), 10 medium-grade (CINII), 24 high-grade (CINIII), and 17 chronic cervicitis. $BLOCK-iT^{TM}$ U6 RNAi Entry Vector $pENTR^{TM}$/U6-E6 and E7 was constructed and transfected the entry clone directly into the mammalian cell line 293FT. Then the HPV 16-positive SiHa human cervical carcinoma cell line was infected with RNAi recombinant lentivirus. RT-PCR and Western blotting were used to determine the expression of TLR9 in both SiHa and HPV 16 E6 and E7 silenced SiHa cells. Results: Immunohistochemical staining showed that TLR9 expression was undetectable (88.2%) or weak (11.8%) in chronic cervicitis tissues. However, variable staining was observed in the basal layer of all normal endocervical glands. TLR9 expression, which was mainly observed as cytoplasmic staining, gradually increased in accordance with the histopathological grade in the following order: chronic cervicitis (2/17, 11.8%)

키워드

참고문헌

  1. Akira S, Takeda K (2004). Toll-like receptor signalling. Nat Rev Immunol, 4, 499-511. https://doi.org/10.1038/nri1391
  2. Akira S, Uematsu S, Takeuchi O (2006). Pathogen recognition and innate immunity. Cell, 124, 783-01. https://doi.org/10.1016/j.cell.2006.02.015
  3. Cohen J (2005). Pubic health High hopes and dilemmas for a cervical cancer vaccine. Science, 308, 618-21. https://doi.org/10.1126/science.308.5722.618
  4. Clifford GM, Smith JS, Plummer M, et al (2003). Human papillomavirus types in invasive cervical cancer worldwide: a meta-analysis. Br J Cancer, 88, 63-73. https://doi.org/10.1038/sj.bjc.6600688
  5. Dolganiuc A, Garcia C, Kodys K, et al (2006). Distinct Toll-like receptor expression in monocytes and T cells in chronic HCV infection. World J Gastroenterol, 12, 1198-04.
  6. Daud II, Scott ME, Ma Y, et al (2011). Association between tolllike receptor expression and human papillomavirus type 16 persistence. Int J Cancer, 128, 879-86. https://doi.org/10.1002/ijc.25400
  7. Ferlay J, Autier P, Boniol M, et al (2007). Estimates of the cancer incidence and mortality in Europe in 2006. Ann Oncol, 18, 581-92.
  8. Frisch M, Biggar RJ, Goedert JJ (2000). Human papillomavirusassociated cancers in patients with human immunodeficiency virus infection and acquired immunodeficiency syndrome. J Natl Cancer Inst, 92, 1500-10. https://doi.org/10.1093/jnci/92.18.1500
  9. Groskreutz DJ, Monick MM, Powers LS, et al (2006). Respiratory syncytial virus induces TLR3 protein and protein kinase R: leading to increased double-stranded RNA responsiveness in airway epithelial cells. J Immunol, 176, 1733-40. https://doi.org/10.4049/jimmunol.176.3.1733
  10. Huang B, Zhao J, Unkeless JC, et al (2008). TLR signaling by tumor and immune cells: a double-edged sword. Oncogene, 27, 218-24. https://doi.org/10.1038/sj.onc.1210904
  11. Horsmans Y, Berg T, Desager JP, et al (2005). Isatoribine an agonist of TLR7: reduces plasma virus concentration in chronic hepatitis C infection. Hepatology, 42, 724-31. https://doi.org/10.1002/hep.20839
  12. Hasan UA, Bates E, Takeshita F, et al (2007). TLR9 expression and function is abolished by the cervical cancer-associated human papillomavirus type 16. J Immunol, 178, 3186-97. https://doi.org/10.4049/jimmunol.178.5.3186
  13. IIvesaro JM, Merrell MA, Swain TM, et al (2007). Toll like receptor-9 agonists stimulate prostate cancer invasion in vitro. Prostate, 67, 774-81. https://doi.org/10.1002/pros.20562
  14. Krieg AM (2008). Toll-like receptor 9 (TLR9) agonists in the treatment of cancer. Oncogene, 27, 161-7. https://doi.org/10.1038/sj.onc.1210911
  15. Kim WY, Lee JW, Choi JJ, et al (2008). Increased expression of Toll-like receptor 5 during progression of cervical neoplasia. Int J Gynecol Cancer, 18, 300-5. https://doi.org/10.1111/j.1525-1438.2007.01008.x
  16. LIU KJ, LIU JW, LI XR, et al (2008). Epidemiology study of risk factors on Uigur and Han cervical cancer in Xinjiang (J). J Xinjiang Med Univ, 31, 1335-8.
  17. Lenert PS (2010). Classification, mechanisms of action and therapeutic applications of inhibitory oligonucleotides for toll-like receptors (TLR) 7 and 9. Mediators Inflamm, 2010, 986596.
  18. Lee JW, Choi JJ, Seo ES, et al (2007). Increased toll-like receptor 9 expression in cervical neoplasia. Mol Carcinog, 46, 941-7. https://doi.org/10.1002/mc.20325
  19. Matijevic T, Pavelic J (2010). Toll-like receptors: cost or benefit for cancer. Curr Pharm, 16, 1081-90. https://doi.org/10.2174/138161210790963779
  20. Mishra A, Bharti AC, Varghese P, et al (2006). Differential expression and activation of NF-kappaB family proteins during oral carcinogenesis: role of high risk human papillomavirus infection. Int J Cancer, 119, 2840-50. https://doi.org/10.1002/ijc.22262
  21. Mukherjee S, Siddiqui MA, Dayal S, et al (2014). Epigallocatechin-3-gallate suppresses proinflammatory cytokines and chemokines induced by Toll-like receptor 9 agonists in prostate cancer cells. J Inflamm Res, 17, 89-101.
  22. Nees M, Geoghegan JM, Hyman T, et al (2001). Papillomavirus type 16 oncogenes down-regulate expression of interferonresponsive genes and up-regulate proliferation-associated and NF-kappaB-responsive genes in cervical keratinocytes. J Virol, 75, 4283-96. https://doi.org/10.1128/JVI.75.9.4283-4296.2001
  23. Ostor AG (1993). Natural history of cervical intraepithelial neoplasia: a critical review. Int J Gynecol Pathol, 12, 186-92. https://doi.org/10.1097/00004347-199304000-00018
  24. Ren T, Wen ZK, Liu ZM, et al (2007). Functional expression of TLR9 is associated to the metastatic potential of human lung cancer cell: functional active role of TLR9 on tumor metastasis. Cancer Biol Ther, 6, 1704-9. https://doi.org/10.4161/cbt.6.11.4826
  25. Stanley MA, Pett MR, Coleman N (2007). HPV: from infection to cancer. Biochem Soc Trans, 35, 1456-60. https://doi.org/10.1042/BST0351456
  26. Sato Y, Goto Y, Narita N, et al (2009). Cancer cells expressing toll-like receptors and the tumor microenvironment. Cancer Microenviron, 2, 205-14. https://doi.org/10.1007/s12307-009-0022-y
  27. Suzuke L, Peng YH, Zhou K, et al (2006). The analysis of pathogenetic tendency of cervical cancer in various ethnic women in Xinjiang. J Xinjiang Med Univ, 29, 569-71.
  28. Tezcan S, Ozgur D, Ulger M, et al (2014). Human papillomavirus genotype distribution and E6/ E7 oncogene expression in Turkish women with cervical cytological findings. Asian Pac J Cancer Prev, 15, 3997-4003. https://doi.org/10.7314/APJCP.2014.15.9.3997
  29. Tommasino M (2001). Early genes of human papillomaviruses: In Encyclopedic Reference of Cancer. Springer-Verlag, Heidelberg, 262-272.
  30. Takeshita F, Gursel I, Ishii KJ, et al (2004). Signal transduction pathways mediated by the interaction of CpG DNA with Toll-like receptor 9. Semin Immunol, 16, 17-22. https://doi.org/10.1016/j.smim.2003.10.009
  31. Takeshita F, Suzuki K, Sasaki S, et al (2004). Transcriptional regulation of the human TLR9 gene. J Immunol, 173, 2552-61. https://doi.org/10.4049/jimmunol.173.4.2552
  32. Wu XM, Liu X, Jiao QF, et al (2014). Cytotoxic T lymphocytes elicited by dendritic cell-targeted delivery of human papillomavirus type-16 E6/E7 fusion gene exert lethal effects on CaSki cells. Asian Pac J Cancer Prev, 15, 2447-51. https://doi.org/10.7314/APJCP.2014.15.6.2447
  33. Wang D, Xiao PL, Duan HX, et al (2012). Peptidoglycans Promotes Human Leukemic THP-1 Cell Apoptosis and Differentiation. Asian Pacific J Cancer Prev, 13, 6409-13. https://doi.org/10.7314/APJCP.2012.13.12.6409
  34. Yang BH, Bray FI, Parkin DM, et al (2004). Cervical cancer as a priority for prevention in different world regions: an evaluation using years of life lost. Int J Cancer, 109, 418-24. https://doi.org/10.1002/ijc.11719
  35. Wang D, Xiao PL, Duan HX, et al (2012). Lack of association of three common polymorphisms in Toll-like receptors (TLRs), TLR2+597T>C, +1350C>T and Arg753Gln with cancer risk: a meta-analysis. Asian Pac J Cancer Prev, 14, 5871-76. https://doi.org/10.7314/APJCP.2013.14.10.5871
  36. Zhang GQ, LIU KJ, Lai XJ, et al (2003). Distribution of malignant tumor patients in hospital from 1989 to 2002 in the Affiliated Tumor Hospital of Xinjiang Medical University. J Xinjiang Med Univ, 26, 393-5.
  37. Zhang SQ, Yakup K, Abliz G, et al (2009). The study of the relationships between HPV multiple infection and cervical cancer of Uygur Women in Xinjiang. J Xinjiang Med Univ, 32, 525-8.

피인용 문헌

  1. TLR9 gene polymorphism −1486T/C (rs187084) is associated with uterine cervical neoplasm in Mexican female population vol.143, pp.12, 2017, https://doi.org/10.1007/s00432-017-2495-2
  2. The Associations between Toll-Like Receptor 9 Gene Polymorphisms and Cervical Cancer Susceptibility vol.2018, pp.1466-1861, 2018, https://doi.org/10.1155/2018/9127146
  3. Therapeutic potential of toll‐like receptors in treatment of gynecological cancers pp.1521-6551, 2019, https://doi.org/10.1002/iub.2011