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

doi:10.19401/j.cnki.1007-3639.2016.12.001

中国癌症杂志 ›› 2016, Vol. 26 ›› Issue (12): 961-967.doi: 10.19401/j.cnki.1007-3639.2016.12.001

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

任春霞¹，马锦琪¹，吕祝武¹，娄雪玲²，吕　蓓¹，杨　恭^3,4

1 江苏省无锡市人民医院妇产科，江苏无锡 214023 ；
2 河南省郑州市人民医院妇科，河南郑州 450003 ；
3 复旦大学附属肿瘤医院肿瘤研究所，复旦大学上海医学院肿瘤学系，上海200032 ；
4 复旦大学附属第五人民医院中心实验室，上海200240

出版日期:2016-12-30 发布日期:2017-01-23
通信作者: 吕　蓓　E-mail: lvbei@wuxiph.com
基金资助:
国家自然科学基金青年项目(NSFC 81402153)；无锡市卫计委指导性项目(ZD201401)；南京医科大学面上基金(2012NJMU179)。

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 Gong^3,4,5

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

Published:2016-12-30 Online:2017-01-23
Contact: LV Bei E-mail: lvbei@wuxiph.com

摘要/Abstract

摘要： 背景与目的：肿瘤微环境中衰老的癌相关成纤维细胞(cancer-associated fibroblasts，CAFs)介导上皮肿瘤的转移和放化疗抵抗，而CAFs分泌的炎性细胞因子IL-6可能促进宫颈癌的侵袭和放疗抵抗，但其作用机制并不清楚。该研究旨在探讨IL-6对CAFs衰老及宫颈癌上皮细胞侵袭与放疗抵抗的作用。方法：以宫颈癌CAFs、宫颈组织正常成纤维细胞(normal fibroblasts，NFs)、宫颈癌细胞系HeLa、Siha和ME180为材料，采用IL-6、STAT3和Notch抑制剂处理不同细胞，用细胞染色、免疫荧光、蛋白[质]印迹法(Western blot)和流式细胞术等方法测定细胞衰老、STAT3、Notch信号、细胞侵袭能力和对放射线诱导的细胞凋亡变化。结果：CAFs条件培养基(conditioned medium，CM)或IL-6可以激活STAT3和Notch信号诱导细胞衰老或促进宫颈癌细胞的侵袭能力；CAFs与宫颈癌细胞混合培养能促进宫颈癌细胞的侵袭，但IL-6抗体、STAT3抑制剂S31-201或Notch抑制剂DAPT处理细胞则会抑制宫颈癌细胞的侵袭。IL-6/STAT3作为Notch信号的上游分子，可能主要通过自分泌或旁分泌的方式上调成纤维细胞或癌细胞中Notch信号关键配体Jagged-1而活化Notch信号，最后赋予宫颈癌细胞对放射线的抵抗作用。结论：CAFs在肿瘤微环境中可能通过IL-6/STAT3活化Notch信号诱导宫颈癌上皮细胞的侵袭和放疗抵抗，靶向STAT3/Notch信号相关分子有可能提高宫颈癌的放疗效果。

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

任春霞,马锦琪,吕祝武,等. 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[J]. 中国癌症杂志, 2016, 26(12): 961-967.

REN Chunxia, MA Jinqi, Lü Zhuwu, et al. 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[J]. China Oncology, 2016, 26(12): 961-967.

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[4]	徐　瞳,胡丽娜,郭显智,等. 5-氮杂胞苷可通过抑制Notch1通路诱导食管癌细胞凋亡[J]. 中国癌症杂志, 2018, 28(10): 726-732.
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[6]	任春霞,徐娜,宋亚琴,赵敏,陈亚萍,吕蓓,杨恭. 癌相关成纤维细胞通过Gro-α激活NF-кB核转位和VEGF表达促进卵巢癌的生长[J]. 中国癌症杂志, 2014, 24(5): 321-328.
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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

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

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