Neurotensin/IL-8 pathway orchestrates local inflammatory response and tumor invasion by inducing M2 polarization of Tumor-Associated macrophages and epithelial-mesenchymal transition of hepatocellular carcinoma cells

doi:10.1080/2162402X.2018.1440166

	Neurotensin/IL-8 pathway orchestrates local inflammatory response and tumor invasion by inducing M2 polarization of Tumor-Associated macrophages and epithelial-mesenchymal transition of hepatocellular carcinoma cells
	Xiao, Pei 1,2; Long, Xinxin 3; Zhang, Lijie 1,2; Ye, Yingnan 1; Guo, Jincheng 4,5; Liu, Pengpeng 1; Zhang, Rui 1; Ning, Junya 1,2; Yu, Wenwen 2; Wei, Feng 2; Yu, Jinpu 1,2
	2018
发表期刊	ONCOIMMUNOLOGY
ISSN	2162-402X
卷号	7 期号:7 页码:19
摘要	We previously demonstrated that neurotensin (NTS) induces local inflammation and promotes tumor invasion in hepatocellular carcinoma (HCC). However, the underlying molecular mechanisms are not clear. In this study, positive correlations between NTS and interleukin (IL)-8 were identified at both the mRNA and protein levels in 71 fresh HCC tissues and 100 paraffin-embedded HCC tissues. Furthermore, significant correlations were determined among the co-expression of NTS and IL-8, infiltration of inflammatory cells and enhanced epithelial-mesenchymal transition (EMT) of HCC cells. NTS-induced IL-8 production was associated with activation of the mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-B) pathways rather than the protein kinase C (PKC) and phosphoinositide-3 kinase (PI3K) pathways, whose specific antagonists significantly inhibited activation of the NTS/IL-8 pathway. IL-8, which promoted EMT and HCC invasion both in vitro and in vivo, was produced by NTS-induced HCC cells and was effectively attenuated by blocking IL-8 receptors in vitro. Moreover, HCC-derived IL-8 attracted more CD68(+) tumor-associated macrophages (TAMs) and CD66b(+) polymorphonuclear neutrophils (PMNs) to the local microenvironment, displaying enhanced cytokine secretion and phagocytosis. IL-8 stimulated the M2 polarization of TAMs, which promoted the EMT and invasive potential of HCC cells. Blockage of the IL-8 receptor, NTR1 receptor or both significantly reduced HCC metastases in tumor-bearing mouse models via inhibiting EMT. In summary, aberrant activation of the NTS/IL-8 pathway in HCC dramatically stimulated the invasive potential of HCC cells. HCC-derived IL-8 promoted a pro-oncogenic inflammatory microenvironment by inducing M2-type TAMs and indirectly promoting EMT, which might be a valuable therapeutic target to prevent tumor progression.
关键词	Neurotensin interleukin-8 hepatocellular carcinoma epithelial-mesenchymal transition tumor-associated macrophages
DOI	10.1080/2162402X.2018.1440166
收录类别	SCI
语种	英语
资助项目	National Natural Science Foundation of China[81472473] ; National Natural Science Foundation of China[81272360] ; National Key Scientific and Technological Project of China[2015BAI12B12] ; National Key Scientific and Technological Project of China[2015BAI12B15] ; Scientific and Technological Project of Tianjin, China[13ZCZCSY20300] ; Key Project of Tianjin Health and Family Planning Commission[16KG126]
WOS研究方向	Oncology ; Immunology
WOS类目	Oncology ; Immunology
WOS记录号	WOS:000433549100005
出版者	TAYLOR & FRANCIS INC
引用统计	被引频次：113[WOS] [WOS记录] [WOS相关记录]
文献类型	期刊论文
条目标识符	http://119.78.100.204/handle/2XEOYT63/5244
专题	中国科学院计算技术研究所期刊论文_英文
通讯作者	Yu, Jinpu
作者单位	1.Tianjin Med Univ Canc Inst & Hosp, Canc Mol Diagnost Core, Key Lab Canc Prevent & Therapy, Natl Clin Res Ctr Caner, Tianjin, Peoples R China 2.Tianjin Med Univ Canc Inst & Hosp, Dept Immunol, Natl Clin Res Ctr Caner, Key Lab Canc Immunol & Biotherapy, Tianjin, Peoples R China 3.Tengzhou Cent Peoples Hosp, Dept Oncol, Tengzhou, Shandong, Peoples R China 4.Chinese Acad Sci, Inst Comp Technol, Bioinformat Res Grp, Beijing, Peoples R China 5.Chinese Acad Sci, Inst Comp Technol, Hlth Big Data, Beijing, Peoples R China
推荐引用方式 GB/T 7714	Xiao, Pei,Long, Xinxin,Zhang, Lijie,et al. Neurotensin/IL-8 pathway orchestrates local inflammatory response and tumor invasion by inducing M2 polarization of Tumor-Associated macrophages and epithelial-mesenchymal transition of hepatocellular carcinoma cells[J]. ONCOIMMUNOLOGY,2018,7(7):19.
APA	Xiao, Pei.,Long, Xinxin.,Zhang, Lijie.,Ye, Yingnan.,Guo, Jincheng.,...&Yu, Jinpu.(2018).Neurotensin/IL-8 pathway orchestrates local inflammatory response and tumor invasion by inducing M2 polarization of Tumor-Associated macrophages and epithelial-mesenchymal transition of hepatocellular carcinoma cells.ONCOIMMUNOLOGY,7(7),19.
MLA	Xiao, Pei,et al."Neurotensin/IL-8 pathway orchestrates local inflammatory response and tumor invasion by inducing M2 polarization of Tumor-Associated macrophages and epithelial-mesenchymal transition of hepatocellular carcinoma cells".ONCOIMMUNOLOGY 7.7(2018):19.