期刊
JOURNAL OF CELLULAR BIOCHEMISTRY
卷 119, 期 11, 页码 9419-9432出版社
WILEY
DOI: 10.1002/jcb.27259
关键词
chemotherapy resistance; hepatocellular carcinoma (HCC); interleukin-6 (IL-6); signal transducer and activator of transcription 3 (STAT3) signaling pathway; macrophage; metastasis
资金
- 2017 Guangdong Natural Science Fund [2017A030313905]
- 2014 People's Livelihood Science and Technology Project, Special Project on the Integration of Industry, Education and Research of Guangzhou City [2014Y200509]
- 2017 Guangdong Medical Science and Technology Fund [A2017102]
Human cancers, including hepatocellular carcinoma (HCC), are characterized by a high degree of drug resistance in chemotherapy. However, the underlying molecular mechanism remains unknown. To the role of interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) signaling pathway in the regulation of macrophage polarization, M1-type and M2-type macrophages were separately induced using lipopolysaccharide and interleukin-4 (IL-4), and we found that the IL-6/STAT3 signaling pathway was inhibited in M1-type macrophages but activated in M2-type macrophages. After anti-IL-6-treated macrophages were separately induced by lipopolysaccharide and IL-4, we found that the inhibition of IL-6/STAT3 signaling pathway turned macrophages into M1-type. Co-culture with M1-type macrophages reduced HCC cell viability, proliferation, invasion, migration, drug resistance, but increased apoptosis. Co-culture with M2-type macrophages yielded reciprocal results. The inhibition of IL-6/STAT3 signaling pathway mediated by anti-IL6 was shown to significantly enhance the effects of M1-type macrophages on HCC cells and rescue HCC cells from co-culture with M2-type macrophages. Tumor xenografts of co-cultured HCC cells were established in nude mice and the results showed that the inhibition of IL-6/STAT3 signaling pathway mediated by anti-IL6 was found to reduce tumor formation of HCC cells co-cultured with M1- or M2-type macrophages and lung metastases. The current study reveals a novel mechanism of IL-6/STAT3 signaling pathway in the regulation of macrophage polarization, thus contributing to HCC metastasis and drug resistance in chemotherapy.
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