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Human umbilical cord mesenchymal stem cell-derived exosomes carrying miR-1827 downregulate SUCNR1 to inhibit macrophage M2 polarization and prevent colorectal liver metastasis

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Abstract

microRNA-1827 (miR-1827) is proposed to be enriched in exosomes from mesenchymal stem cells (MSCs-Exos). A recent study has addressed the suppressive effect of exosomes from human umbilical cord mesenchymal stem cells (hUC-MSCs-Exos) on colorectal cancer (CRC) metastasis. Hence, our study aims at investigating whether hUC-MSCs-Exos can modulate the liver metastasis in CRC by mediating miR-1827. Transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA) were used to identify hUC-MSCs-Exos. Using gain- and loss-of-function approaches, the expression of miR-1827 and succinate receptor 1 (SUCNR1) was altered. Consequently, the biological functions of CRC cells were assessed by CCK-8 and Transwell assays and macrophage M2 polarization was assayed by flow cytometry. Dual-luciferase reporter assay was applied to clarify interaction between miR-1827 and SUCNR1. CRC cells were incubated with hUC-MSCs-Exos and tumor-bearing mice were injected with hUC-MSCs-Exos to examine the effects on CRC cell growth and metastasis. SUCNR1, lowly expressed in CRC, could promote CRC cell growth and macrophage M2 polarization. miR-1827 could target SUCNR1 and hence suppress the progression and metastasis of CRC. hUC-MSCs-Exos carried miR-1827 to inhibit M2 macrophage polarization by downregulating SUCNR1 expression, and inhibited proliferating, migrating and invading properties of CRC cells. Furthermore, hUC-MSCs-Exos carrying miR-1827 blocked CRC liver metastasis in vivo. These findings indicate hUC-MSCs-Exos as an inhibitor of M2 macrophage polarization and liver metastasis in CRC through inducing miR-1827-targeted inhibition of SUCNR1. This provides a theoretical basis for understanding the mechanisms underlying Exos-based target therapy for CRC.

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Acknowledgements

Not applicable.

Funding

This study was supported by National Natural Science Foundation of China (82102497), Guangdong Medical Research Fund(A2020032), Guangdong Basic and Applied Basic Research Fund Project (2020A1515110633), Guangzhou Science and Technology Plan Project (202102020151), Research Fund for the Doctoral Program of GDPH (2020bq02,2020bq03).

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Authors and Affiliations

  1. Department of Laboratory Medicine, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, 106 Zhongshan 2nd Rd, Yuexiu District, 510080, Guangzhou, Guangdong Province, P. R. China

    Jierong Chen, Jianhong Ma, Jiaxin Lin, Dandan Zhu, Jinxin Lai & Bing Gu

  2. Prenatal Diagnostic Center and Cord Blood Bank, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, 510000, Guangzhou, P. R. China

    Ziyue Li

  3. Department of Laboratory Medicine, Central People’s Hospital of Zhanjiang, Guangdong Medical University, Zhanjiang Central Hospital, 524045, Zhanjiang, P. R. China

    Caifeng Yue

  4. Research Center of Medical Sciences, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, 510080, Guangzhou, China

    Lixue Cao & Ran An

  5. Zhanjiang Institute of Clinical Medicine, Central People’s Hospital of Zhanjiang, Guangdong Medical University, Zhanjiang Central Hospital, 524045, Zhanjiang, Guangdong Province, P. R. China

    Yunmiao Guo

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  1. Jierong Chen
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Contributions

JRC and JHM conceived and designed research JRC, JHM and JX Lin performed experiments ZYL, CFY, RA and JX Lai analyzed data DDZ, YMG and BG interpreted results of experiments; ZYL and CFY prepared figures JRC, ZYL, CFY, DDZ, RA and JX Lai drafted manuscript JHM, JX Lin, YMG, BG and LXC edited and revised manuscript JRC, ZYL, CFY, JHM, JX Lin, DDZ, RA, JX Lai, YMG and BG approved final version of manuscript.

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Correspondence to Yunmiao Guo or Bing Gu.

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Chen, J., Li, Z., Yue, C. et al. Human umbilical cord mesenchymal stem cell-derived exosomes carrying miR-1827 downregulate SUCNR1 to inhibit macrophage M2 polarization and prevent colorectal liver metastasis. Apoptosis 28, 549–565 (2023). https://doi.org/10.1007/s10495-022-01798-x

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