Theranostics 2021; 11(8):3932-3947. doi:10.7150/thno.53412

Research Paper

Exosomal miR-500a-5p derived from cancer-associated fibroblasts promotes breast cancer cell proliferation and metastasis through targeting USP28

Bing Chen2*, Yuting Sang1*, Xiaojin Song1, Dong Zhang1, Lijuan Wang2, Wenjing Zhao2, Yiran Liang1, Ning Zhang1, Qifeng Yang1,2,3✉

1. Department of Breast Surgery, General Surgery, Qilu Hospital of Shandong University.
2. Pathology Tissue Bank, Qilu Hospital of Shandong University.
3. Research Institute of Breast Cancer, Shandong University.
*These authors contributed equally to this work.

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Citation:
Chen B, Sang Y, Song X, Zhang D, Wang L, Zhao W, Liang Y, Zhang N, Yang Q. Exosomal miR-500a-5p derived from cancer-associated fibroblasts promotes breast cancer cell proliferation and metastasis through targeting USP28. Theranostics 2021; 11(8):3932-3947. doi:10.7150/thno.53412. Available from https://www.thno.org/v11p3932.htm

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Abstract

The tumor microenvironment contributes to tumor progression and metastasis. Cancer-associated fibroblasts (CAFs) form a major cellular component of the tumor microenvironment. In this study, we further explored the mechanisms underlying the tumor-promoting roles of CAFs.

Methods: Patient-derived CAFs and normal fibroblasts (NFs) were isolated from breast carcinomas and adjacent normal breast tissue. Exosomes were isolated by ultracentrifugation and CAF-derived exosomal microRNAs were screened using next-generation sequencing technology. MiR-500a-5p expression was assessed by quantitative real-time polymerase chain reaction (qRT-PCR) and in situ hybridization; Tumor cell proliferation was determined by MTT assays and three-dimensioned (3D) cultures, and tumor metastasis was determined by Transwell assays in vitro. In vivo assays were performed in a nude mouse subcutaneous xenograft model.

Results: We confirmed that CAF-derived exosomes significantly promoted the proliferation and metastasis of breast cancer cells. MiR-500a-5p was highly expressed in MDA-MB-231 and MCF7 cells treated with CAF-derived exosomes. The upregulation of miR-500a-5p was also confirmed in CAFs and CAF-derived exosomes. MiR-500a-5p was transferred from CAFs to the cancer cells, and subsequently promoted proliferation and metastasis by binding to ubiquitin-specific peptidase 28 (USP28).

Conclusions: The present study demonstrates that CAFs promote breast cancer progression and metastasis via exosomal miR-500a-5p and indicate that inhibiting CAF-derived miR-500a-5p is an alternative modality for the treatment of breast cancer.

Keywords: cancer-associated fibroblasts, exosome, miR-500a-5p, breast cancer, USP28