Interleukin-32? inhibits tumor-promoting effects of macrophage-secreted CCL18 in breast cancer.

ABSTRACT: BACKGROUND:Tumor-associated macrophages can promote breast cancer metastasis by secreting cytokines and growth factors. Interleukin (IL)-32?, a newly identified IL-32 isoform, was previously shown to down-regulate various proinflammatory factors of macrophages. Here, we report the presence of IL-32? in breast cancer tissues and evaluate its effects on macrophage-regulated breast cancer metastasis. METHODS:RT-qPCR was used to analyze the mRNA expression of IL-32?, Chemokine (C-C motif) ligand 18 (CCL18) in breast cancer tissues. In vitro cell-based experiments using IL-32?-expressing MDA-MB-231 cells were conducted to examine the effects of IL-32? on metastasis and its molecular signaling. In vivo xenograft, immunohistochemistry, and optical imaging models were generated to support in vitro and clinical findings. RESULTS:The clinical data displayed opposite expression patterns of CCL18 and IL-32? mRNA in macrophage-infiltrated breast tumor tissues compared with those in the other tissues tested. In MDA-MB-231 cells, IL-32? overexpression attenuated migration, invasion, tumor-promoting factors, and increased epithelial markers levels upon treatment with conditioned media from THP-1-derived macrophages. Additionally, IL-32? expression in a xenograft model led to a remarkable decrease in tumor size and macrophage-stimulated tumor promotion. This inhibition was mediated through a direct interaction with protein kinase C-? (PKC?), subsequently eliminating the downstream factors STAT3 and NF-?B. Blocking CCL18 during co-culture of macrophages and breast cancer cells reduced the levels of breast cancer progression-related factors and PKC? downstream signaling suggesting CCL18 as the main macrophage-secreted factors triggering the signaling pathway inhibited by IL-32?. CONCLUSIONS:Our findings demonstrate a novel role of IL-32? as an intracellular modulator to suppress macrophage-promoted breast cancer progression by targeting CCL18-dependent signaling.

SUBMITTER: Pham TH 

PROVIDER: S-EPMC6534939 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature