Theranostics 2021; 11(14):6847-6859. doi:10.7150/thno.51864

Research Paper

Cancer-derived exosomal miR-138-5p modulates polarization of tumor-associated macrophages through inhibition of KDM6B

Jing Xun1,2#, Lingfang Du1#, Ruifang Gao1, Long Shen1, Dekun Wang1, Lichun Kang1, Chuan'ai Chen1, Zhujun Zhang1, Yuying Zhang1, Shijing Yue1, Shuxin Feng3, Rong Xiang1, Xue Mi1✉, Xiaoyue Tan1✉

1. School of Medicine, Nankai University, Tianjin 300071, China.
2. Tianjin Nankai Hospital, Tianjin, 300100, China.
3. Department of Orthopedics, Tianjin First Central Hospital, Tianjin, 300071, China.
#These authors equally contributed to this work.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Citation:
Xun J, Du L, Gao R, Shen L, Wang D, Kang L, Chen C, Zhang Z, Zhang Y, Yue S, Feng S, Xiang R, Mi X, Tan X. Cancer-derived exosomal miR-138-5p modulates polarization of tumor-associated macrophages through inhibition of KDM6B. Theranostics 2021; 11(14):6847-6859. doi:10.7150/thno.51864. Available from https://www.thno.org/v11p6847.htm

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Abstract

Rationale: Differential activation of macrophages correlates closely with tumor progression, and the epigenetic factor lysine demethylase 6B (KDM6B, previously named JMJD3) mediates the regulation of macrophage polarization through an unknown mechanism.

Methods: We developed a suspension coculture system comprising breast cancer cells and macrophages and used RT-qPCR and western blotting to measure KDM6B expression. Bioinformatics and luciferase reporter assays were used to identify candidate microRNAs of cancer cells responsible for the downregulation of KDM6B. To determine if exosomes mediated the transfer of miR-138-5p between cancer cells to macrophages, we treated macrophages with exosomes collected from the conditioned medium of cancer cells. The effects of exosomal miR-138-5p on macrophage polarization were measured using RT-qPCR, flow cytometry, and chromatin immunoprecipitation assays. We employed a mouse model of breast cancer, metastatic to the lung, to evaluate the effects on tumor metastasis of macrophages treated with miR-138-5p-enriched exosomes. To develop a diagnostic evaluation index, the levels of exosomal miR-138-5p in samples from patients with breast cancer were compared to those of controls.

Results: Coculture of breast cancer cells led to downregulation of KDM6B expression in macrophages. Cancer cell-derived exosomal miR-138-5p inhibited M1 polarization and promoted M2 polarization through inhibition of KDM6B expression in macrophages. Macrophages treated with exosomal miR-138-5p promoted lung metastasis, and the level of circulating exosomal miR-138-5p positively correlated with the progression of breast cancer.

Conclusion: Our data suggest that miR-138-5p was delivered from breast cancer cells to tumor-associated macrophages via exosomes to downregulate KDM6B expression, inhibit M1 polarization, and stimulate M2 polarization. Therefore, exosomal miR-138-5p represents a promising prognostic marker and target for the treatment of breast cancer.

Keywords: tumor-associated macrophages, lysine demethylase 6B (KDM6B), microRNA-138-5p, exosomes, macrophage polarization