China Oncology ›› 2016, Vol. 26 ›› Issue (12): 961-967.doi: 10.19401/j.cnki.1007-3639.2016.12.001

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Mechanistic study of cancer-associated fibroblast senescence and cervical cancer cell invasiveness and radio-resistance conferred by IL-6 through activation of STAT3 and Notch signaling

REN Chunxia1, MA Jinqi1, LÜ Zhuwu1, LOU Xueling2, LÜ Bei1, YANG Gong3,4,5   

  1. 1. Department of Gynecology and Obstetrics, The People’s Hospital of Wuxi, Jiang Su, 214023; 2. Deparment of Gynecology, The People’s Hospital of Zhengzhou, Henan, 450003; 3. Cancer Institute, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032; 4. Central Laboratory, The Fifth People’s Hospital of Shanghai, Fudan University, Shanghai, 200240
  • Online:2016-12-30 Published:2017-01-23
  • Contact: LV Bei E-mail:

Abstract: 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.

Key words: Cancer-associated fibroblast, Interleukin-6, Senescence, STAT3, Notch, Radio-resistance