Purpose: The present study aimed to investigate the role of FPR1 and the downstream effectors such as NF-κB and IL-6/8 in the development of cervical cancer.
Patients and methods: FPR1 protein expression was detected via immunohistochemical staining in tissue microarrays containing cervical cancer tissues from 185 patients. Following FPR1 silencing in SiHa cells using lentiviral siRNA delivery, biological characteristics and tumor formation were evaluated in vitro and in vivo, respectively. Phosphorylated NF-κB levels were detected by Western blotting, while IL-6 and IL-8 secretion were detected by ELISA in both FPR1 knockdown and control SiHa cells. Human umbilical vein endothelial cell tube formation assays were performed to evaluate the angiogenesis-promoting ability of IL-6 and IL-8 secretion in FPR1 knockdown and control SiHa cells. Neovascularization, proliferation and apoptosis markers were detected by immunohistochemical staining to analyze the tumorigenic role of FPR1.
Results: Immunohistochemistry of cervical cancer tissues from 185 patients revealed high FPR1 expression levels in patients with advanced-stage disease and/or poor prognosis. Compared with control cells, cervical cancer cells in which FPR1 was silenced exhibited inhibition of cell invasion, migration and proliferation and higher levels of apoptosis. NF-κB was inhibited in FPR1 knockdown in SiHa cells. IL-6/8 upregulation by FPR1 activation stimulated angiogenesis. FPR1 deficiency inhibited the tumorigenicity of cervical cancer cells in nude mice. FPR1, IL-6, IL-8, CD31 and Ki67 levels were all reduced, whereas cleaved caspase-3 was upregulated, in the FPR1 knockdown group compared with the levels in the control group.
Conclusion: High FPR1 expression was associated with advanced stage and poor prognosis in cervical cancer patients. FPR1 activation induced NF-κB nuclear translocation to promote cervical cancer development through the upregulation of IL-6 and IL-8 expression. Inhibiting FPR1 activity may thus have potential therapeutic value in cervical cancer patients.
Keywords: cervical cancer, FPR1, IL-6, IL-8