Interleukin-32θ 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)-32θ, a newly identified IL-32 isoform, was previously shown to down-regulate various proinflammatory factors of macrophages. Here, we report the presence...
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doaj-a4875e9cbde74092bd308f955d9d494d2020-11-25T03:23:36ZengBMCCell Communication and Signaling1478-811X2019-05-0117111410.1186/s12964-019-0374-yInterleukin-32θ inhibits tumor-promoting effects of macrophage-secreted CCL18 in breast cancerThu-Huyen Pham0Yesol Bak1Taeho Kwon2Sae-Bom Kwon3Jae-Wook Oh4Jong-Hyung Park5Yang-Kyu Choi6Jin Tae Hong7Do-Young Yoon8Department of Bioscience and Biotechnology, Konkuk UniversityDepartment of Bioscience and Biotechnology, Konkuk UniversityPrimate Resource Center, Division of Bioinfrastructure, Korea Research Institute of Bioscience and Biotechnology (KRIBB)Department of Bioscience and Biotechnology, Konkuk UniversityDepartment of Stem Cell and Regenerative Biotechnology, Konkuk UniversityDepartment of Laboratory Animal Medicine, College of Veterinary Medicine, Konkuk UniversityDepartment of Laboratory Animal Medicine, College of Veterinary Medicine, Konkuk UniversityCollege of Pharmacy and Medical Research Center, Chungbuk National UniversityDepartment of Bioscience and Biotechnology, Konkuk UniversityAbstract Background Tumor-associated macrophages can promote breast cancer metastasis by secreting cytokines and growth factors. Interleukin (IL)-32θ, a newly identified IL-32 isoform, was previously shown to down-regulate various proinflammatory factors of macrophages. Here, we report the presence of IL-32θ 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-32θ, Chemokine (C-C motif) ligand 18 (CCL18) in breast cancer tissues. In vitro cell-based experiments using IL-32θ-expressing MDA-MB-231 cells were conducted to examine the effects of IL-32θ 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-32θ mRNA in macrophage-infiltrated breast tumor tissues compared with those in the other tissues tested. In MDA-MB-231 cells, IL-32θ overexpression attenuated migration, invasion, tumor-promoting factors, and increased epithelial markers levels upon treatment with conditioned media from THP-1-derived macrophages. Additionally, IL-32θ 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-δ (PKCδ), subsequently eliminating the downstream factors STAT3 and NF-κB. Blocking CCL18 during co-culture of macrophages and breast cancer cells reduced the levels of breast cancer progression-related factors and PKCδ downstream signaling suggesting CCL18 as the main macrophage-secreted factors triggering the signaling pathway inhibited by IL-32θ. Conclusions Our findings demonstrate a novel role of IL-32θ as an intracellular modulator to suppress macrophage-promoted breast cancer progression by targeting CCL18-dependent signaling.http://link.springer.com/article/10.1186/s12964-019-0374-yIL-32θMacrophageBreast cancer metastasisCCL18PKCδSTAT3 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Thu-Huyen Pham Yesol Bak Taeho Kwon Sae-Bom Kwon Jae-Wook Oh Jong-Hyung Park Yang-Kyu Choi Jin Tae Hong Do-Young Yoon |
spellingShingle |
Thu-Huyen Pham Yesol Bak Taeho Kwon Sae-Bom Kwon Jae-Wook Oh Jong-Hyung Park Yang-Kyu Choi Jin Tae Hong Do-Young Yoon Interleukin-32θ inhibits tumor-promoting effects of macrophage-secreted CCL18 in breast cancer Cell Communication and Signaling IL-32θ Macrophage Breast cancer metastasis CCL18 PKCδ STAT3 |
author_facet |
Thu-Huyen Pham Yesol Bak Taeho Kwon Sae-Bom Kwon Jae-Wook Oh Jong-Hyung Park Yang-Kyu Choi Jin Tae Hong Do-Young Yoon |
author_sort |
Thu-Huyen Pham |
title |
Interleukin-32θ inhibits tumor-promoting effects of macrophage-secreted CCL18 in breast cancer |
title_short |
Interleukin-32θ inhibits tumor-promoting effects of macrophage-secreted CCL18 in breast cancer |
title_full |
Interleukin-32θ inhibits tumor-promoting effects of macrophage-secreted CCL18 in breast cancer |
title_fullStr |
Interleukin-32θ inhibits tumor-promoting effects of macrophage-secreted CCL18 in breast cancer |
title_full_unstemmed |
Interleukin-32θ inhibits tumor-promoting effects of macrophage-secreted CCL18 in breast cancer |
title_sort |
interleukin-32θ inhibits tumor-promoting effects of macrophage-secreted ccl18 in breast cancer |
publisher |
BMC |
series |
Cell Communication and Signaling |
issn |
1478-811X |
publishDate |
2019-05-01 |
description |
Abstract Background Tumor-associated macrophages can promote breast cancer metastasis by secreting cytokines and growth factors. Interleukin (IL)-32θ, a newly identified IL-32 isoform, was previously shown to down-regulate various proinflammatory factors of macrophages. Here, we report the presence of IL-32θ 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-32θ, Chemokine (C-C motif) ligand 18 (CCL18) in breast cancer tissues. In vitro cell-based experiments using IL-32θ-expressing MDA-MB-231 cells were conducted to examine the effects of IL-32θ 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-32θ mRNA in macrophage-infiltrated breast tumor tissues compared with those in the other tissues tested. In MDA-MB-231 cells, IL-32θ overexpression attenuated migration, invasion, tumor-promoting factors, and increased epithelial markers levels upon treatment with conditioned media from THP-1-derived macrophages. Additionally, IL-32θ 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-δ (PKCδ), subsequently eliminating the downstream factors STAT3 and NF-κB. Blocking CCL18 during co-culture of macrophages and breast cancer cells reduced the levels of breast cancer progression-related factors and PKCδ downstream signaling suggesting CCL18 as the main macrophage-secreted factors triggering the signaling pathway inhibited by IL-32θ. Conclusions Our findings demonstrate a novel role of IL-32θ as an intracellular modulator to suppress macrophage-promoted breast cancer progression by targeting CCL18-dependent signaling. |
topic |
IL-32θ Macrophage Breast cancer metastasis CCL18 PKCδ STAT3 |
url |
http://link.springer.com/article/10.1186/s12964-019-0374-y |
work_keys_str_mv |
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