IL‐6/STAT3 pathway intermediates M1/M2 macrophage polarization during the development of hepatocellular carcinoma. Issue 11 (17th July 2018)

• Record Type: Journal Article
• Authors: Yin, Zi; Ma, Tingting; Lin, Ye; Lu, Xin; Zhang, Chuanzhao; Chen, Sheng; Jian, Zhixiang
• Is Part Of: Journal of cellular biochemistry. Volume 119:Issue 11(2018)
• Page Start: 9419
• Page End: 9432
• Publication Date: 2018-07-17
• Subjects: chemotherapy resistance -- hepatocellular carcinoma (HCC) -- interleukin‐6 (IL‐6)/signal transducer and activator of transcription 3 (STAT3) signaling pathway -- macrophage -- metastasis; Cytochemistry -- Periodicals; 572
• DOI: 10.1002/jcb.27259
• Languages: English
• ISSNs: 0730-2312

Abstract

Abstract: 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. Abstract : The IL‐6/STAT3 signaling pathway reduced cell viability, colony formation capacity, invasion, migration, chemotherapy resistance and xenograft tumor growth, and enhanced cellular apoptosis in mouse HCC Hepal‐6 cells with macrophage polarization to the M1 phenotype.