CXCL10/CCL2 signaling pathway mediates the development of cervical cancer in tumor microenvironment

Abstract:

Objective To investigate the role of C-X-C motif chemokine ligand 10（CXCL10）/C-C motif chemokine ligand 2（CCL2） signaling pathway in the development of cervical cancer（CC） in tumor microenvironment.Methods In vitro cervical cancer Hela cells were transfected with shRNA（sh-CXCL10） and CXCL10 cDNA（CXCL10） targeting CXCL10 gene，respectively.Cell proliferation was evaluated by EdU analysis and cell invasion was detected by Transwell assay.THP-1 cell differentiation was induced with phorbol 12-myristic acid 13-acetate（PMA）.The cells were co-cultured with Hela cells（5×10⁶ cells） transfected with the lentivirus or plasmid at a ratio of 1∶4 for 48 h.The number of CD206+ macrophages was determined by flow cytometry and STAT3/NF-κB signal expression was measured by Western blot.Results Compared with the NC group，Hela cells with CXCL10 over-expression co-cultured with THP-1 cells showed increased proliferation，migration，and invasion（P<0.05），and the ratio of CD206+ macrophages increased significantly（P<0.05）.Hela cells with CXCL10 knock-down co-cultured with THP-1 cells showed the opposite results.Compared with NC group，the CXCL10 co-culture system showed significant increases in the expression of p-STAT3，p-NF-κB，and CCL2（P<0.05）.Compared with the sh-NC group，the sh-CXCL10 co-culture system showed significant decreases in the expression of p-STAT3，p-NF-κB，and CCL2（P<0.05）.Conclusion Up-regulation of CXCL10 in CC cells promotes M2 polarization of macrophages in tumor microenvironment.The mechanism may be related to activation of STAT3/NF-κB/CCL2 signal transduction pathway in macrophages，which leads to the enhancement of proliferation，migration，and invasion of CC cells.