Oncotarget

Research Papers:

Leptin promotes migration and invasion of breast cancer cells by stimulating IL-8 production in M2 macrophages

Hong Cao, Yunxiu Huang, Lin Wang, Hong Wang, Xueli Pang, Kuangfa Li, Weiqi Dang, Hao Tang, Lan Wei, Min Su, Cuiping Tang and Tingmei Chen _

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Oncotarget. 2016; 7:65441-65453. https://doi.org/10.18632/oncotarget.11761

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Abstract

Hong Cao1,*, Yunxiu Huang1,*, Lin Wang1, Hong Wang1, Xueli Pang1, Kuangfa Li1, Weiqi Dang1, Hao Tang1, Lan Wei1, Min Su1, Cuiping Tang1, Tingmei Chen1

1Department of Laboratory Medicine, Key Laboratory of Diagnostic Medicine, Ministry of Education Chongqing Medical University, Chongqing, China

*These authors contributed equally to this work

Correspondence to:

Tingmei Chen, email: chentingmei@sohu.com

Keywords: breast cancer, IL-8, invasion, leptin, migration

Received: January 31, 2016     Accepted: August 13, 2016     Published: August 31, 2016

ABSTRACT

This study aims to investigate the mechanisms underlying leptin-mediated crosstalk between tumor-associated macrophages (M2 macrophages) and breast cancer cells. THP1 human leukemic monocytes were induced to differentiate into M2 macrophages by PMA (100 nM) and IL-4 (20 ng/mL). Quantitative RT-PCR and Western blot revealed that leptin (100 nM) significantly increased the expression of leptin receptor (ObR) in the M2 macrophages (P < 0.01) and stimulated interleukin (IL)-8 expression in the M2 macrophages, mouse macrophage cells RAW264.7, and primary mouse peritoneal macrophages in a dose- and time-dependent manner. Leptin-induced IL-8 production was sensitive to the ERK inhibitor PD980590 (10 μmol/L), p38 MAPK inhibitor SB203580 (20 μmol/L), and anti-ObR neutralizing antibody (4 μg/mL). Leptin (100 ng/mL) substantially increased the phosphorylation of p38 and ERK1/2. Thus, leptin may induce IL-8 production in M2 macrophages by interacting with ObR to activate the p38 and ERK signaling pathways. Scratch and transwell chamber assay showed that both recombinant IL-8 and leptin-induced M2 macrophage-derived IL-8 promoted the migration and invasion of human breast cancer cells MCF7 and MDA-MB-231 (All P < 0.01). In a nude mice xenograft model of breast cancer (n = 5 per group), injection of leptin (0.1 μg/g) dramatically increased tumor volume and mass, reduced survival, exacerbated pulmonary metastasis, and elevated IL-8 and Ki67 expression in the tumor tissue (All P < 0.05) compared with PBS injection. Depletion of mouse macrophage by Clophosome®-clodronate liposome and injection of anti-mouse IL-8 neutralizing antibodies in the xenograft tumor significantly attenuated those leptin-mediated stimulations (All P < 0.05). These findings indicate that leptin may promote tumor growth and metastasis by stimulating IL-8 production in tumor-associated macrophage.


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