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Elevating microRNA-1-3p shuttled by cancer-associated fibroblasts-derived extracellular vesicles suppresses breast cancer progression and metastasis by inhibiting GLIS1

Cancer Gene Therapy volume 28, pages 634–648 (2021)Cite this article

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Abstract

Cancer-associated fibroblasts (CAFs) play supporting roles in tumor progression by releasing microvesicles that transmit oncogenic cargoes. Indeed, extracellular vesicles (EVs) have emerged as important vehicles to deliver proteins, messenger RNAs (mRNAs), and microRNAs (miRs) between cells. In this study, we aimed to outline the role and function of CAFs-derived EVs carrying miR-1-3p in breast cancer. We first experimentally determined downregulated miR-1-3p in breast cancer tissues. EVs were isolated from CAFs extracted from breast cancer tissues, which showed downregulated miR-1-3p expression relative to EVs derived from normal fibroblasts (NFs). In a co-culture system, miR-1-3p cargo was transported into breast cancer cells via CAF-derived EVs. In gain-of-function experiments, the elevation of miR-1-3p in breast cancer cells inhibited cell viability, invasion, migration, and epithelial-to-mesenchymal transition, and suppressed tumor formation and metastasis. Furthermore, EVs derived from CAFs transfected with miR-1-3p mimic were more effective in transferring miR-1-3p to suppress cancer progression and metastasis. Krüppel-like zinc-finger protein Gli-similar 1 (GLIS1) was predicted to be a putative target of miR-1-3p, which was subsequently confirmed by dual-luciferase reporter assay. We then demonstrated that overexpression of GLIS1 neutralized the effects of miR-1-3 on the development of breast cancer in vitro. These findings shed light on the underlying mechanism by which CAFs-derived EVs carrying miR-1-3p mediate the progression and metastasis of breast cancer, and highlight the potential of miR-1-3p shuttled by CAFs-derived EVs serving as a therapeutic target for breast cancer.

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Fig. 1: CAFs and NFs were successfully extracted from breast cancer tissues, and EVs were successfully isolated from CAFs and NFs.
Fig. 2: miR-1-3p could be transferred to breast cancer cells via CAFs-derived EVs.
Fig. 3: miR-1-3p overexpression impaired breast cancer progression and metastasis in vivo and in vitro.
Fig. 4: Upregulation of EV-carried miR-1-3p secreted from CAFs inhibited breast cancer development and metastasis in vivo and in vitro.
Fig. 5: GLIS1 is a target gene of miR-1-3p in breast cancer cells.
Fig. 6: miR-1-3p inhibited breast cancer development by repressing GLIS1 in vitro.
Fig. 7: Mechanism of CAFs-derived EVs carrying miR-1-3p in breast cancer with the involvement of GLIS1.

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The datasets generated/analyzed during this study are available.

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Acknowledgements

The authors sincerely appreciate all members participated in this work.

Funding

This work was supported by the National Natural Science Foundation of China (No. 81760482, 82060479), Natural Science Foundation of Ningxia (2020AAC03417, 2018AAC03165) and Changzhou Sci & Tech Program (CJ20200068).

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Author notes

  1. These authors contributed equally: Shuang Tao, Hong Li, Xiuzhen Ma

Authors and Affiliations

  1. Department of Breast Surgery, Changzhou No. 7 People’s Hospital, 213000, Changzhou, P. R. China

    Shuang Tao

  2. Department of Surgical Oncology, General Hospital of Ningxia Medical University, 750004, Yinchuan, P. R. China

    Hong Li, Xiuzhen Ma & Jinping Li

  3. Ningxia Medical University, 750004, Yinchuan, P. R. China

    Yunfei Ma, Jiale He & Yali Gao

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  1. Shuang Tao
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Contributions

XZM and JPL wrote the paper; ST, HL, and XZM designed the research; YFM, JLH, and YLG performed the research; ST, HL, and XZM analyzed the data; all authors contributed equally to this work.

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Correspondence to Jinping Li.

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Tao, S., Li, H., Ma, X. et al. Elevating microRNA-1-3p shuttled by cancer-associated fibroblasts-derived extracellular vesicles suppresses breast cancer progression and metastasis by inhibiting GLIS1. Cancer Gene Ther 28, 634–648 (2021). https://doi.org/10.1038/s41417-020-00244-x

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