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

Int J Oncol. 2020 Apr;56(4):921-931. doi: 10.3892/ijo.2020.4983. Epub 2020 Feb 12.

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.

Keywords: prostaglandin E2; dendritic cells; inhibited migration; E6; cervical lesions.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Cell Line, Tumor
  • Cell Movement*
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism
  • Dinoprostone / chemistry
  • Dinoprostone / immunology
  • Dinoprostone / metabolism*
  • Female
  • Human papillomavirus 16 / isolation & purification*
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Middle Aged
  • Oncogene Proteins, Viral / genetics
  • Oncogene Proteins, Viral / metabolism*
  • Papillomavirus Infections / complications*
  • Papillomavirus Infections / virology
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Uterine Cervical Neoplasms / genetics
  • Uterine Cervical Neoplasms / immunology
  • Uterine Cervical Neoplasms / pathology*
  • Uterine Cervical Neoplasms / virology
  • Xenograft Model Antitumor Assays
  • Young Adult

Substances

  • E6 protein, Human papillomavirus type 16
  • Oncogene Proteins, Viral
  • Repressor Proteins
  • Dinoprostone