E6‑regulated overproduction of prostaglandin E2 may inhibit migration of dendritic cells in human papillomavirus 16‑positive cervical lesions

Huang,Jie; Diao,Ge; Zhang,Qiong; Chen,Yajie; Han,Jian; Guo,Jianxin

doi:10.3892/ijo.2020.4983

E6‑regulated overproduction of prostaglandin E2 may inhibit migration of dendritic cells in human papillomavirus 16‑positive cervical lesions

Authors:
- Jie Huang
- Ge Diao
- Qiong Zhang
- Yajie Chen
- Jian Han
- Jianxin Guo
View Affiliations

Affiliations: Department of Obstetrics and Gynecology, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing 400042, P.R. China, Institute of Burn Research, Southwest Hospital, State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University, Chongqing 400038, P.R. China
Published online on: February 12, 2020 https://doi.org/10.3892/ijo.2020.4983
Pages: 921-931
Copyright: © Huang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Continuous human papillomavirus (HPV) infection is a critical cause of cervical lesions; however, the specific mechanism is currently not clear. E6 is one of the most important oncoproteins associated with HPV, which regulates synthases in the production of prostaglandin E2 (PGE2). Notably, PGE2 has been reported to be upregulated in cervical lesions. An insufficient number of mature dendritic cells (DCs), which is unable to cause an effective immune response, is an important cause of cervical lesions. Therefore, this study explored the possible causes of HPV16‑positive cervical lesions by identifying the relationship between E6, PGE2 and DCs. Firstly, the distribution and status of DCs in clinical biopsy specimens and animal models were analyzed with immunohistochemistry and flow cytometry, which demonstrated that the migratory ability of DCs was inhibited in HPV16‑positive cervical lesions. Furthermore, using immunohistochemistry, western blotting and ELISA, it was revealed that as the degree of cervical lesions increased, the expression of PGE2 and its synthases increased. Subsequently, as determined using Transwell and 3D migration assays, it was revealed that a high concentration of PGE2 inhibited the migration of DCs, which may explain the phenomenon observed in cervical lesions. Notably, E6 was identified to regulate PGE2 expression. The in vivo experiments indicated that E6 may increase the expression levels of PGE2 in cervical lesions, which could eventually induce inhibition of the migration of DCs. In conclusion, the present study suggested that E6 regulated overproduction of PGE2, which may induce inhibition of DC migration in HPV16‑positive cervical lesions.

View Figures

View References

1	Martin-Gayo E and Yu XG: Role of Dendritic Cells in Natural Immune Control of HIV-1 Infection. Front Immunol. 10:13062019. View Article : Google Scholar : PubMed/NCBI
2	Carenza C, Calcaterra F, Oriolo F, Di Vito C, Ubezio M, Della Porta MG, Mavilio D and Della Bella S: Costimulatory molecules and immune checkpoints are differentially expressed on different subsets of dendritic cells. Front Immunol. 10:13252019. View Article : Google Scholar : PubMed/NCBI
3	Hayati AR and Zulkarnaen M: An immunohistochemical study of CD1a and CD83-positive infiltrating dendritic cell density in cervical neoplasia. Int J Gynecol Pathol. 26:83–88. 2007. View Article : Google Scholar : PubMed/NCBI
4	Poindexter NJ, Sahin A, Hunt KK and Grimm EA: Analysis of dendritic cells in tumor-free and tumor-containing sentinel lymph nodes from patients with breast cancer. Breast Cancer Res. 6:R408–R415. 2004. View Article : Google Scholar : PubMed/NCBI
5	Ishigami S, Natsugoe S, Uenosono Y, Hata Y, Nakajo A, Miyazono F, Matsumoto M, Hokita S and Aikou T: Infiltration of antitumor immunocytes into the sentinel node in gastric cancer. J Gastrointest Surg. 7:735–739. 2003. View Article : Google Scholar : PubMed/NCBI
6	Greenhough A, Smartt HJ, Moore AE, Roberts HR, Williams AC, Paraskeva C and Kaidi A: The COX-2/PGE2 pathway: Key roles in the hallmarks of cancer and adaptation to the tumour micro-environment. Carcinogenesis. 30:377–386. 2009. View Article : Google Scholar : PubMed/NCBI
7	Wang MT, Honn KV and Nie D: Cyclooxygenases, prostanoids, and tumor progression. Cancer Metastasis Rev. 26:525–534. 2007. View Article : Google Scholar : PubMed/NCBI
8	Lee EJ, Kim SJ, Hahn YI, Yoon HJ, Han B, Kim K, Lee S, Kim KP, Suh YG, Na HK, et al: 15-Keto prostaglandin E2 suppresses STAT3 signaling and inhibits breast cancer cell growth and progression. Redox Biol. 23:1011752019. View Article : Google Scholar :
9	Uefuji K, Ichikura T and Mochizuki H: Cyclooxygenase-2 expression is related to prostaglandin biosynthesis and angio-genesis in human gastric cancer. Clin Cancer Res. 6:135–138. 2000.PubMed/NCBI
10	Watson J and Chuah SY: Prostaglandins, steroids and human mammary cancer. Eur J Cancer Clin Oncol. 21:1051–1055. 1985. View Article : Google Scholar : PubMed/NCBI
11	Sales KJ, Katz AA, Davis M, Hinz S, Soeters RP, Hofmeyr MD, Millar RP and Jabbour HN: Cyclooxygenase-2 expression and prostaglandin E(2) synthesis are up-regulated in carcinomas of the cervix: A possible autocrine/paracrine regulation of neoplastic cell function via EP2/EP4 receptors. J Clin Endocrinol Metab. 86:2243–2249. 2001. View Article : Google Scholar : PubMed/NCBI
12	Saalbach A, Janik T, Busch M, Herbert D, Anderegg U and Simon JC: Fibroblasts support migration of monocyte-derived dendritic cells by secretion of PGE2 and MMP-1. Exp Dermatol. 24:598–604. 2015. View Article : Google Scholar : PubMed/NCBI
13	Yen JH, Khayrullina T and Ganea D: PGE2-induced metallo-proteinase-9 is essential for dendritic cell migration. Blood. 111:260–270. 2008. View Article : Google Scholar
14	Li Y, Huang K, Ji PL, Song L and Liu HT: Cervical Infection of Oncogenic Human Papillomavirus (HPV) Types in Beijing, China. Biomed Environ Sci. 29:734–741. 2016.PubMed/NCBI
15	Song D, Li H, Li H and Dai J: Effect of human papillomavirus infection on the immune system and its role in the course of cervical cancer. Oncol Lett. 10:600–606. 2015. View Article : Google Scholar : PubMed/NCBI
16	Guess JC and McCance DJ: Decreased migration of Langerhans precursor-like cells in response to human keratinocytes expressing human papillomavirus type 16 E6/E7 is related to reduced macrophage inflammatory protein-3alpha production. J Virol. 79:14852–14862. 2005. View Article : Google Scholar : PubMed/NCBI
17	Caberg JH, Hubert P, Herman L, Herfs M, Roncarati P, Boniver J and Delvenne P: Increased migration of Langerhans cells in response to HPV16 E6 and E7 oncogene silencing: Role of CCL20. Cancer Immunol Immunother. 58:39–47. 2009. View Article : Google Scholar
18	Subbaramaiah K and Dannenberg AJ: Cyclooxygenase-2 transcription is regulated by human papillomavirus 16 E6 and E7 oncoproteins: Evidence of a corepressor/coactivator exchange. Cancer Res. 67:3976–3985. 2007. View Article : Google Scholar : PubMed/NCBI
19	Lutz MB, Kukutsch N, Ogilvie AL, Rössner S, Koch F, Romani N and Schuler G: An advanced culture method for generating large quantities of highly pure dendritic cells from mouse bone marrow. J Immunol Methods. 223:77–92. 1999. View Article : Google Scholar : PubMed/NCBI
20	Han P, Hanlon D, Sobolev O, Chaudhury R and Edelson RL: Ex vivo dendritic cell generation-A critical comparison of current approaches. Int Rev Cell Mol Biol. 349:251–307. 2019. View Article : Google Scholar : PubMed/NCBI
21	Baratelli FE, Heuzé-Vourc'h N, Krysan K, Dohadwala M, Riedl K, Sharma S and Dubinett SM: Prostaglandin E2-dependent enhancement of tissue inhibitors of metalloproteinases-1 production limits dendritic cell migration through extracellular matrix. J Immunol. 173:5458–5466. 2004. View Article : Google Scholar : PubMed/NCBI
22	Ghittoni R, Accardi R, Hasan U, Gheit T, Sylla B and Tommasino M: The biological properties of E6 and E7 oncoproteins from human papillomaviruses. Virus Genes. 40:1–13. 2010. View Article : Google Scholar
23	Narisawa-Saito M and Kiyono T: Basic mechanisms of high-risk human papillomavirus-induced carcinogenesis: Roles of E6 and E7 proteins. Cancer Sci. 98:1505–1511. 2007. View Article : Google Scholar : PubMed/NCBI
24	Boldrini NT, Freitas LB, Coutinho AR, Loureiro FZ, Spano LC and Miranda AE: High-grade cervical lesions among women attending a reference clinic in Brazil: Associated factors and comparison among screening methods. PLoS One. 9:e1021692014. View Article : Google Scholar : PubMed/NCBI
25	Mazumder Indra D, Singh RK, Mitra S, Dutta S, Chakraborty C, Basu PS, Mondal RK, Roychoudhury S and Panda CK: Genetic and epigenetic changes of HPV16 in cervical cancer differentially regulate E6/E7 expression and associate with disease progression. Gynecol Oncol. 123:597–604. 2011. View Article : Google Scholar : PubMed/NCBI
26	Leong CM, Doorbar J, Nindl I, Yoon HS and Hibma MH: Loss of epidermal Langerhans cells occurs in human papillomavirus alpha, gamma, and mu but not beta genus infections. J Invest Dermatol. 130:472–480. 2010. View Article : Google Scholar
27	Tran Janco JM, Lamichhane P, Karyampudi L and Knutson KL: Tumor-infiltrating dendritic cells in cancer pathogenesis. J Immunol. 194:2985–2991. 2015. View Article : Google Scholar : PubMed/NCBI
28	Khaiboullina SF, Morzunov SP, Hall MR, De Meirleir KL, Rizvanov AA and Lombardi VC: Human dendritic cells transfected with a human papilloma virus-18 construct display decreased mobility and upregulated cytokine production. Int J Oncol. 43:1701–1709. 2013. View Article : Google Scholar : PubMed/NCBI
29	Fitzgerald DW, Bezak K, Ocheretina O, Riviere C, Wright TC, Milne GL, Zhou XK, Du B, Subbaramaiah K, Byrt E, et al: The effect of HIV and HPV coinfection on cervical COX-2 expression and systemic prostaglandin E2 levels. Cancer Prev Res (Phila). 5:34–40. 2012. View Article : Google Scholar
30	Tsujii M, Kawano S, Tsuji S, Sawaoka H, Hori M and DuBois RN: Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell. 93:705–716. 1998. View Article : Google Scholar : PubMed/NCBI
31	Karpisheh V, Nikkhoo A, Hojjat-Farsangi M, Namdar A, Azizi G, Ghalamfarsa G, Sabz G, Yousefi M, Yousefi B and Jadidi-Niaragh F: Prostaglandin E2 as a potent therapeutic target for treatment of colon cancer. Prostaglandins Other Lipid Mediat. 144:1063382019. View Article : Google Scholar : PubMed/NCBI
32	Tsujii M and DuBois RN: Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endo-peroxide synthase 2. Cell. 83:493–501. 1995. View Article : Google Scholar : PubMed/NCBI
33	Sharma S, Yang SC, Zhu L, Reckamp K, Gardner B, Baratelli F, Huang M, Batra RK and Dubinett SM: Tumor cyclooxy-genase-2/prostaglandin E2-dependent promotion of FOXP3 expression and CD4+ CD25+ T regulatory cell activities in lung cancer. Cancer Res. 65:5211–5220. 2005. View Article : Google Scholar : PubMed/NCBI
34	Tang F, Zhang R and Wang J: Cyclooxygenase-2-Mediated Up-Regulation of Mitochondrial Transcription Factor A Mitigates the Radio-Sensitivity of Cancer Cells. Int J Mol Sci. 20:E12182019. View Article : Google Scholar : PubMed/NCBI
35	Balan R, Amălinei C, Giuşcă SE, Ditescu D, Gheorghiţă V, Crauciuc E and Căruntu ID: Immunohistochemical evaluation of COX-2 expression in HPV-positive cervical squamous intraepithelial lesions. Rom J Morphol Embryol. 52:39–43. 2011.PubMed/NCBI
36	Hara S, Kamei D, Sasaki Y, Tanemoto A, Nakatani Y and Murakami M: Prostaglandin E synthases: Understanding their pathophysiological roles through mouse genetic models. Biochimie. 92:651–659. 2010. View Article : Google Scholar : PubMed/NCBI
37	Herfs M, Herman L, Hubert P, Minner F, Arafa M, Roncarati P, Henrotin Y, Boniver J and Delvenne P: High expression of PGE2 enzymatic pathways in cervical (pre)neoplastic lesions and functional consequences for antigen-presenting cells. Cancer Immunol Immunother. 58:603–614. 2009. View Article : Google Scholar
38	Mattila S, Tuominen H, Koivukangas J and Stenbäck F: The terminal prostaglandin synthases mPGES-1, mPGES-2, and cPGES are all overexpressed in human gliomas. Neuropathology. 29:156–165. 2009. View Article : Google Scholar : PubMed/NCBI
39	Scandella E, Men Y, Gillessen S, Förster R and Groettrup M: Prostaglandin E2 is a key factor for CCR7 surface expression and migration of monocyte-derived dendritic cells. Blood. 100:1354–1361. 2002. View Article : Google Scholar : PubMed/NCBI
40	Bruckner M, Dickel D, Singer E and Legler DF: Converse regulation of CCR7-driven human dendritic cell migration by prostaglandin E₂ and liver X receptor activation. Eur J Immunol. 42:2949–2958. 2012. View Article : Google Scholar : PubMed/NCBI
41	Legler DF, Krause P, Scandella E, Singer E and Groettrup M: Prostaglandin E2 is generally required for human dendritic cell migration and exerts its effect via EP2 and EP4 receptors. J Immunol. 176:966–973. 2006. View Article : Google Scholar : PubMed/NCBI
42	Scandella E, Men Y, Legler DF, Gillessen S, Prikler L, Ludewig B and Groettrup M: CCL19/CCL21-triggered signal transduction and migration of dendritic cells requires prostaglandin E2. Blood. 103:1595–1601. 2004. View Article : Google Scholar
43	Shimabukuro-Vornhagen A, Liebig TM, Koslowsky T, Theurich S and von Bergwelt-Baildon MS: The ratio between dendritic cells and T cells determines whether prostaglandin E2 has a stimulatory or inhibitory effect. Cell Immunol. 281:62–67. 2013. View Article : Google Scholar : PubMed/NCBI
44	Rubio MT, Means TK, Chakraverty R, Shaffer J, Fudaba Y, Chittenden M, Luster AD and Sykes M: Maturation of human monocyte-derived dendritic cells (MoDCs) in the presence of prostaglandin E2 optimizes CD4 and CD8 T cell-mediated responses to protein antigens: Role of PGE2 in chemokine and cytokine expression by MoDCs. Int Immunol. 17:1561–1572. 2005. View Article : Google Scholar : PubMed/NCBI
45	Spaggiari GM, Abdelrazik H, Becchetti F and Moretta L: MSCs inhibit monocyte-derived DC maturation and function by selectively interfering with the generation of immature DCs: Central role of MSC-derived prostaglandin E2. Blood. 113:6576–6583. 2009. View Article : Google Scholar : PubMed/NCBI
46	Sá-Nunes A, Bafica A, Lucas DA, Conrads TP, Veenstra TD, Andersen JF, Mather TN, Ribeiro JM and Francischetti IM: Prostaglandin E2 is a major inhibitor of dendritic cell maturation and function in Ixodes scapularis saliva. J Immunol. 179:1497–1505. 2007. View Article : Google Scholar : PubMed/NCBI
47	Kim YB, Kim GE, Cho NH, Pyo HR, Shim SJ, Chang SK, Park HC, Suh CO, Park TK and Kim BS: Overexpression of cyclooxygenase-2 is associated with a poor prognosis in patients with squamous cell carcinoma of the uterine cervix treated with radiation and concurrent chemotherapy. Cancer. 95:531–539. 2002. View Article : Google Scholar : PubMed/NCBI
48	Hugo de Almeida V, Guimarães IDS, Almendra LR, Rondon AMR, Tilli TM, de Melo AC, Sternberg C and Monteiro RQ: Positive crosstalk between EGFR and the TF-PAR2 pathway mediates resistance to cisplatin and poor survival in cervical cancer. Oncotarget. 9:30594–30609. 2018.PubMed/NCBI