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EVs delivery of miR-1915-3p improves the chemotherapeutic efficacy of oxaliplatin in colorectal cancer

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Abstract

Purpose

Oxaliplatin is a crucial component of the combinatorial chemotherapeutic standard of care for advanced colorectal cancer (CRC). Unfortunately, a serious barrier to effective oxaliplatin treatment is drug resistance due to epithelial-mesenchymal transitioning (EMT). Interestingly, stable oxaliplatin-resistant CRC cell lines show differential expression of miR-1915-3p; thus, this microRNA may represent a potential modifier of oxaliplatin resistance in CRC cells.

Methods

miR-1915-3p was over-expressed in oxaliplatin-resistant CRC cells and a non-tumorigenic intestinal cell line (FHC) via lentiviral transduction. Extracellular vesicles (EVs) were purified from transduced FHC cells and co-incubated with CRC cells. Expression levels of miR-1915-3p and other RNA species were assessed by RT-qPCR, while protein expression levels were assessed by Western blotting. The effects of miR-1915-3p on CRC viability were evaluated by proliferation, apoptosis assays, and Transwell assays. Effects of miR-1915-3p over-expression on in vivo oxaliplatin sensitivity was tested via murine xenograft models.

Results

miRNA-1915-3p decreased EMT marker expression in oxaliplatin-resistant CRC cell lines and in vivo. FHC cells were able to produce and secrete miR-1915-3p-containing EVs, which we employed to mediate miR-1915-3p delivery to oxaliplatin-resistant CRC cells and increase their oxaliplatin sensitivity in vivo and in vitro. Mechanistically, miR-1915-3p overexpression downregulated the EMT-promoting oncogenes 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) and ubiquitin carboxyl-terminal hydrolase 2 (USP2) as well as upregulated E-cadherin (a cell adhesion mediator). miR-1915-3p’s effects on chemosensitivity and EMT were mediated by its regulation of PFKFB3 and USP2.

Conclusion

Exosomal delivery of miR-1915-3p can improve the chemotherapeutic efficacy of oxaliplatin in CRC cells by suppressing the EMT-promoting oncogenes PFKFB3 and USP2.

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Authors and Affiliations

  1. Department of General Surgery, The Shenzhen Hospital of Southern Medical University, Shenzhen, China

    Zhenhuan Xiao & Qinyuan Liu

  2. Department of Pediatrics, The First Affiliated Hospital of Nanchang University, Nanchang, China

    Yun Liu

  3. Health Management Center, The Shenzhen Hospital of Southern Medical University, Shenzhen, China

    Qun Li

  4. Department of Oncology, The People’s Hospital of Leping City, Jingdezhen, China

    Yong Liu

  5. Department of Oncology, The Third Affiliated Hospital of Nanchang University, Nanchang, China

    Yan Luo

  6. Department of Oncology, The Third Hospital of Nanchang, No. 2 Xiangshannan Road, Nanchang, China

    Songzhi Wei

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  1. Zhenhuan Xiao
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  2. Yun Liu
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  4. Qinyuan Liu
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  5. Yong Liu
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Contributions

Conceived and designed the study: ZX and YL. Performed the experimental procedures: QL and YL. Analyzed the data: ZX, YL, SW, QL and YL. Drafted the manuscript: QL and YL.

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Correspondence to Songzhi Wei.

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Xiao, Z., Liu, Y., Li, Q. et al. EVs delivery of miR-1915-3p improves the chemotherapeutic efficacy of oxaliplatin in colorectal cancer. Cancer Chemother Pharmacol 88, 1021–1031 (2021). https://doi.org/10.1007/s00280-021-04348-5

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  • DOI: https://doi.org/10.1007/s00280-021-04348-5

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