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
10.19401/j.cnki.1007-3639.2016.12.001
- VernacularTitle:IL-6通过活化STAT3/Notch信号促进癌相关成纤维细胞衰老及宫颈癌上皮细胞侵袭与放疗抵抗的机理研究
- Author:
Chunxia REN
;
Jinqi MA
;
Zhuwu LV
;
Xueling LOU
;
Bei LV
;
Gong YANG
- Keywords:
Cancer-associated ifbroblast;
Interleukin-6;
Senescence;
STAT3;
Notch;
Radio-resistance
- From:
China Oncology
2016;26(12):961-967
- CountryChina
- Language:Chinese
-
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.
