Mechanistic study of cancer-associated ifbroblast senescence and cervical cancer cell invasiveness and radio-resistance conferred by IL-6 through activation of STAT3 and Notch signaling / 中国癌症杂志

ABSTRACT

Background and purpose:Senescent cancer-associated ifbroblasts (CAFs) in tumor microenvi-ronment 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 ifbroblasts (NFs) from nor-mal 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, immunolfuorescence, Western blot, and lfow 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 can-cer 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 ifbroblasts 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-re-sistance through IL-6/STAT3-mediated Notch activation, and that targeting of the STAT3/Notch signaling-associated molecules may improve the effcacy of radiotherapy for cervical cancer.