No 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 (PGE 2 ). Notably, PGE 2 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, PGE 2 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 PGE 2 and its synthases increased. Subsequently, as determined using Transwell and 3D migration assays, it was revealed that a high concentration of PGE 2 inhibited the migration of DCs, which may explain the phenomenon observed in cervical lesions. Notably, E6 was identified to regulate PGE 2 expression. The in vivo experiments indicated that E6 may increase the expression levels of PGE 2 in cervical lesions, which could eventually induce inhibition of the migration of DCs. In conclusion, the present study suggested that E6 regulated overproduction of PGE 2 , which may induce inhibition of DC migration in HPV16-positive cervical lesions.

dendritic cells (dcs) are the most potent antigen-presenting cells, and are indispensable in the immune system. Prostaglandin E2 (PGE 2) has been demonstrated to modulate the migration of dcs, but with inconsistent results. The present study, based on our previous research, used murine bone marrow-derived dcs to elucidate the potential regulatory mechanism of PGE 2 on the migration of dcs. The results indicated that PGE 2 served a dual role in regulating the migration of dcs in a dose-dependent manner. High concentrations of PGE 2 inhibited cell migration, whereas low concentrations exhibited the opposite effect. Flow cytometry revealed that the expression of cc chemokine receptor type 7 on the dc surface was increased following treatment with low concentrations of PGE 2 and slightly decreased by high concentrations of PGE 2. The effect of PGE 2 was indicated to be exerted via reorganizing the F-actin cytoskeleton using confocal microscopy. Moreover, the regulatory effect of PGE 2 on the migration of dcs was validated in vivo. Subsequent gene expression profile analyses using RNA-sequencing technology indicated that PGE 2 induced alterations in the expression of multiple downstream genes and signaling pathway molecules associated with cell migration and the cytoskeleton. These findings may provide an improved understanding on the mechanism of dc migration under both pathological and physiological conditions. Moreover, the biological implications of these findings may provide a novel perspective of the immunological surveillance in the progression of different types of diseases.

Transcriptome-based stemness indices analysis reveals platinum-based chemo-theraputic response indicators in advanced-stage serous ovarian cancer,