Background and purpose: Senescent cancer-associated fibroblasts (CAFs) in tumor microenvironment are known to mediate the invasion and radio- or chemo-resistance of epithelial cancers. The inflammatory cytokine IL-6 derived from CAFs may promote the invasion and radio-resistance of epithelial cervical cancer. However

the detailed mechanism is not clear. This study aimed to investigate the effects of IL-6 on CAFs senescence

cervical cancer cell invasiveness and radio-resistance. Methods: CAFs from cervical cancer

normal fibroblasts (NFs) from normal cervical tissues

and cervical cancer cell lines including HeLa

Siha and ME180 were used in this study. Different treatments of cells with IL-6 and inhibitors of STAT3 and Notch were conducted to investigate the alterations of cellular senescence

STAT3/Notch signaling

cell invasiveness

and radiotherapy-induced apoptosis by using cell staining

immunofluorescence

Western blot

and flow cytometery. Results: This study found that the conditioned medium (CM) of CAFs or IL-6 could activate the STAT3 and Notch signaling to promote cellular senescence and cervical cancer cell invasiveness. Co-culture of cervical cancer cells HeLa or Siha along with CAFs also increased the invasiveness of cancer cells

but further treatments of cells by addition of an IL-6 antibody or the inhibitors of STAT3 (S31-201) or Notch (DAPT) blocked the cancer cell invasion. Meanwhile

this study also found that STAT3 functions at the upstream of the Notch signaling to up-regulate Jagged-1

one of the key ligands of Notch in fibroblasts or epithelial cancer cells through IL-6-mediated autocrine or paracrine pathways

which eventually confers the radio-resistance of cervical cancer cells/tissues. Conclusion: CAFs in tumor microenvironment could induce cervical cancer cell invasiveness and radio-resistance through IL-6/STAT3-mediated Notch activation

and that targeting of the STAT3/Notch signaling-associated molecules may improve the efficacy of radiotherapy for cervical cancer.