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Tumor-promoting mechanisms of macrophage-derived extracellular vesicles-enclosed microRNA-660 in breast cancer progression

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Abstract

Introduction

Breast cancer metastasis is the main cause of cancer-related death in women worldwide. Current therapies have remarkably improved the prognosis of breast cancer patients but still fail to manage metastatic breast cancer. Here, the present study was set to explore the role of microRNA (miR)-660 from tumor-associated macrophages (TAMs) in breast cancer, particularly in metastasis.

Materials and methods

We collected breast cancer tissues and isolated their polarized macrophages as well as extracellular vesicles (EVs), in which we measured the expression of miR-660, Kelch-like Protein 21 (KLHL21), and nuclear factor-κB (NF-κB) p65. Breast cancer cells were transfected with miR-660 mimic, miR-660 inhibitor, and sh-KLHL21 and then the cells were co-cultured with EVs or TAMs followed by detection of invasion and migration. Finally, mouse model of breast cancer was established to detect the effect of miR-660 or KLHL21 on metastasis by measuring the lymph node metastasis (LNM) foci in femur and lung.

Results

KLHL21 was poorly expressed, whereas miR-660 was highly expressed in breast cancer tissues and cells. Of note, low KLHL21 expression or high miR-660 expression was related to poor overall survival. EVs-contained miR-660 was identified to bind to KLHL21, reducing the binding between KLHL21 and inhibitor kappa B kinase β (IKKβ) to activate the NF-κB p65 signaling pathway. Interestingly, EV-loaded miR-660 from TAMs could be internalized by breast cancer cells. Moreover, silencing of KLHL21 increased the number of lung LNM foci in vivo, while EVs-contained miR-660 promoted cancerous cell invasion and migration.

Discussion

Taken altogether, our work shows that TAMs-EVs-shuttled miR-660 promotes breast cancer progression through KLHL21-mediated IKKβ/NF-κB p65 axis.

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Data availability

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

miR:

microRNA

TAMs:

Tumor-associated macrophages

EVs:

Extracellular vesicles

KLHL21:

Kelch-like protein 21

IKKβ:

Inhibitor kappa B kinase β

miRNAs:

microRNAs

HE:

Hematoxylin–eosin

RT-qPCR:

Reverse transcription quantitative polymerase chain reaction

GAPDH:

Glyceraldehyde-phosphate dehydrogenase

FBS:

Fetal bovine serum

shKLHL21:

shRNA-Kelch-likeProtein21

NCs:

Negative controls

UTR:

Untranslated region

WT:

Wild type

MUT:

Mutant

IHC:

Immunohistochemistry

RNA-FISH:

RNA-fluorescence in situ hybridization

Co-IP:

Co-immunoprecipitation

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Acknowledgements

We would like to give our sincere appreciation to the reviewers for their helpful comments on this article.

Funding

This work was supported by grants from the Suzhou Health Planning Commission’s Key Clinical Diagnosis and Treatment Program (Grant No. LCZX201606), National Natural Science Foundation of China (Grant No. 81873730) and the Jiangsu Women and Children Health Key Discipline Program (Grant No. FXK201758).

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Author notes

  1. Changchun Li and Ruiqing Li have contributed equally to this work.

Authors and Affiliations

  1. Department of Thyroid and Breast Surgery, The Second Affiliated Hospital of Soochow University, No. 1055, Sanxiang Road, Suzhou, 215000, Jiangsu Province, People’s Republic of China

    Changchun Li & Guoqing Jiang

  2. Department of Thyroid and Breast Surgery, The Affiliated Hospital of Yangzhou University, Yangzhou, 225000, People’s Republic of China

    Ruiqing Li

  3. Department of Thyroid and Breast Surgery, Yancheng City No. 1 People’s Hospital, Yancheng, 224001, People’s Republic of China

    Xingchi Hu & Guangjun Zhou

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  1. Changchun Li
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  4. Guangjun Zhou
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Contributions

(I) Conception and design: CL, RL; (II) Administrative support: CL, XH; (III) Provision of study materials or patients: CL, GJ; (IV) Collection and assembly of data: RL, GZ, GJ; (V) Data analysis and interpretation: RL, XH, GZ; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

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Correspondence to Guoqing Jiang.

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The authors declare that they have no competing interests.

Ethical approval

The experiment was approved by the Ethics Committee of the Second Affiliated Hospital of Soochow University and conducted following the Declaration of Helsinki. All individuals signed informed written consent documents. The experiments involving animals followed the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health.

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Supplementary Information

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Supplementary file1 (DOCX 15 kb)

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Supplementary Fig. 1 The positive controls and NCs of FISH and IHC assays. (JPG 691 kb)

10549_2021_6433_MOESM4_ESM.jpg

Supplementary Fig. 2 Correlation analysis of KLHL21 and miR-660 level (A), KLHL21 and NF-κB p65 level (B) in adjacent normal tissues and breast cancer tissues. (JPG 611 kb)

10549_2021_6433_MOESM5_ESM.jpg

Supplementary Fig. 3 The original gel image of E-cadherin, N-cadherin, MMP-9, MMP-3, and β-actin in breast cancer cells treated with sh-KLHL21, miR-660 inhibitor, or controls. (JPG 1364 kb)

10549_2021_6433_MOESM6_ESM.jpg

Supplementary Fig. 4 HE staining of lung LNM foci from mice following all treatments (A) and quantification of number of metastases in vivoe.Supplementary Fig. 4 HE staining of lung LNM foci from mice following all treatments (A) and quantification of number of metastases in vivo. (JPG 2023 kb)

10549_2021_6433_MOESM7_ESM.jpg

Supplementary Fig. 5 Representative protein blots of Western blot analysis. A, Protein blots of Fig. 3C. B, Protein blots of Fig. 4B. C, Protein blots of Fig. 6B, D, Protein blots of Fig. 6D. E, Protein blots of Fig. 6G. F, Protein blots of Fig. 7A. G, Protein blots of Fig. 7B. (JPG 1314 kb)

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Li, C., Li, R., Hu, X. et al. Tumor-promoting mechanisms of macrophage-derived extracellular vesicles-enclosed microRNA-660 in breast cancer progression. Breast Cancer Res Treat 192, 353–368 (2022). https://doi.org/10.1007/s10549-021-06433-y

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