Novel exosomal miR-46146 transfer oxaliplatin chemoresistance in colorectal cancer
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Oxaliplatin (OX) is widely used for patients with advanced colorectal cancer (CRC). However, most of them will turn out to be OX resistant. Therefore, it is necessary to uncover the causes underlying this phenomenon.
Emerging works have reported that exosomal miRNAs are linked to chemoresistance in many types of cancer. Hence, we separated exosomes from OX sensitive (Exo-S) and resistant CRC cells (Exo-R) by ultracentrifugation and characterized those exosomes by transmission electron microscope and Nanosight NS300. The differentiated miRNAs between Exo-S and Exo-R were identified by small RNA deep sequencing. The expression of miRNA was examined by quantitative real-time PCR (qRT-PCR). The effect of Exo-R and exosomal miR-46146 was determined by CCK-8 assay and flow cytometry (FCM). The target gene of miR-46146 was predicted by computational algorithms and validated by dual luciferase assay.
We found that parental OX sensitive CRC cell acquired increased resistance to the cytotoxicity of OX when they were cocultured with exosomes secreted by OX-resistant CRC. Notably, a novel miRNA miR-46146 was identified and proved to be upregulated in the Exo-R which was internalized by its recipient cells and contributes to the chemoresistance transfer. Furthermore, we demonstrated that PDCD10 was the direct functional target of miR46146 and augmentation of the PDCD10 expression might reverse the effect of Exo-miR-46146-driven chemoresistance.
These results indicate that exosomal miR-46146 functions as a vital mediator of OX resistance by targeting PDCD10 and could be a potential target to re-sensitize CRC cell to OX.
KeywordsColorectal cancer Chemoresistance miR-46146 Exosomes
Oxaliplatin-resistant HCT116 cells
Oxaliplatin-resistant HT29 cells
Exosome from oxaliplatin-sensitive CRC cells
Exosome from oxaliplatin-resistant CRC cells
Quantitative real-time PCR
Transmission electron microscope
Programmed cell death 10
Cerebral cavernous malformation 3
Non-small cell lung cancer
This work was financially supported by the National Natural Science Foundation of China (81602126, 81601843), China Postdoctoral Science Foundation Grant (2018M640464), and the young talents program of Jiangsu Cancer Hospital (QL201805).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
This work is not a research involving human participants and/or animals.
- 3.Watanabe T, Kobunai T, Yamamoto Y, Matsuda K, Ishihara S, Nozawa K, et al. Gene expression signature and response to the use of leucovorin, fluorouracil and oxaliplatin in colorectal cancer patients. Clin Transl Oncol. 2011;13(6):419–25. https://doi.org/10.1007/s12094-011-0676-z.CrossRefPubMedGoogle Scholar
- 6.Schmoll HJ, Twelves C, Sun W, O'Connell MJ, Cartwright T, McKenna E, et al. Effect of adjuvant capecitabine or fluorouracil, with or without oxaliplatin, on survival outcomes in stage III colon cancer and the effect of oxaliplatin on post-relapse survival: a pooled analysis of individual patient data from four randomised controlled trials. Lancet Oncol. 2014;15(13):1481–92. https://doi.org/10.1016/S1470-2045(14)70486-3.CrossRefPubMedPubMedCentralGoogle Scholar
- 9.Ray SDS, Suar M. Molecular mechanism of drug resistance in bacteria, fungi, malaria, and cancer. Cham: Springer; 2017.Google Scholar
- 35.Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Ramanathan RK, Williamson SK, et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol. 2004;22(1):23–30. https://doi.org/10.1200/JCO.2004.09.046.CrossRefPubMedGoogle Scholar
- 39.Hua Y, Zhu Y, Zhang J, Zhu Z, Ning Z, Chen H, et al. miR-122 targets X-linked inhibitor of apoptosis protein to sensitize oxaliplatin-resistant colorectal cancer cells to oxaliplatin-mediated cytotoxicity. Cell Physiol Biochem. 2018;51(5):2148–59. https://doi.org/10.1159/000495832.CrossRefPubMedGoogle Scholar
- 42.Chalmin F, Ladoire S, Mignot G, Vincent J, Bruchard M, Remy-Martin JP, et al. Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells. J Clin Investig. 2010;120(2):457–71. https://doi.org/10.1172/JCI40483.CrossRefPubMedGoogle Scholar
- 47.Lambertz N, El Hindy N, Kreitschmann-Andermahr I, Stein KP, Dammann P, Oezkan N, et al. Downregulation of programmed cell death 10 is associated with tumor cell proliferation, hyperangiogenesis and peritumoral edema in human glioblastoma. BMC Cancer. 2015;15:759. https://doi.org/10.1186/s12885-015-1709-8.CrossRefPubMedPubMedCentralGoogle Scholar