Open Access

N6‑methyladenosine upregulates miR‑181d‑5p in exosomes derived from cancer‑associated fibroblasts to inhibit 5‑FU sensitivity by targeting NCALD in colorectal cancer

  • Authors:
    • Shengli Pan
    • Yingying Deng
    • Jun Fu
    • Yuhao Zhang
    • Zhijin Zhang
    • Xianju Qin
  • View Affiliations

  • Published online on: January 7, 2022     https://doi.org/10.3892/ijo.2022.5304
  • Article Number: 14
  • Copyright: © Pan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Resistance to 5‑Fluorouracil (5‑FU) is a frequent occurrence in patients with colorectal cancer (CRC). MicroRNAs (miRNAs) from cancer‑associated fibroblasts (CAFs)‑secreted exosomes have been associated with 5‑FU sensitivity. The potential molecular mechanism of CAFs‑exosomal miRNAs in CRC remains unclear. The aim of the present study was to elucidate the role of exosomal miRNAs in 5‑FU sensitivity in CRC. Exosomes derived from CAFs were extracted. Exosomal miR‑181d‑5p was identified as a miRNA associated with 5‑FU sensitivity. The putative function of exosomal miR‑181d‑5p was evaluated by ethynyl‑2‑deoxyuridine staining, flow cytometry, RNA immunoprecipitation, luciferase reporter assay, tumor xenograft formation, reverse transcription‑quantitative PCR and western blot analysis. Modification of miR‑181d‑5p by the RNA N6‑methyladenosine (m6A) methyltransferase like (METTL)3 was examined by m6A methylation analysis. The results indicated that m6A modification and METTL3 expression were upregulated in CRC patients. METTL3‑dependent m6A methylation promoted the miR‑181b‑5p process by DiGeorge Syndrome Critical Region 8 (DGCR8) in CAFs. CAFs‑derived exosomes inhibited 5‑FU sensitivity in CRC cells through the METTL3/miR‑181d‑5p axis. A mechanistic study revealed that miR‑181d‑5p directly targeted neurocalcin δ (NCALD) to inhibit the 5‑FU sensitivity of CRC cells. Patients with higher NCALD levels exhibited a higher survival rate. Taken together, METTL3‑dependent m6A methylation was upregulated in CRC to promote the processing of miR‑181d‑5p by DGCR8. This led to increased miR‑181d‑5p expression, which inhibited the 5‑FU sensitivity of CRC cells by targeting NCALD. The results of the present study provided novel insight into exosomal microRNAs in 5‑FU sensitivity in CRC cells. Furthermore, exosomal miR‑181d‑5p may represent a potential prognostic marker for CRC.
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February-2022
Volume 60 Issue 2

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Pan S, Deng Y, Fu J, Zhang Y, Zhang Z and Qin X: N6‑methyladenosine upregulates miR‑181d‑5p in exosomes derived from cancer‑associated fibroblasts to inhibit 5‑FU sensitivity by targeting NCALD in colorectal cancer. Int J Oncol 60: 14, 2022
APA
Pan, S., Deng, Y., Fu, J., Zhang, Y., Zhang, Z., & Qin, X. (2022). N6‑methyladenosine upregulates miR‑181d‑5p in exosomes derived from cancer‑associated fibroblasts to inhibit 5‑FU sensitivity by targeting NCALD in colorectal cancer. International Journal of Oncology, 60, 14. https://doi.org/10.3892/ijo.2022.5304
MLA
Pan, S., Deng, Y., Fu, J., Zhang, Y., Zhang, Z., Qin, X."N6‑methyladenosine upregulates miR‑181d‑5p in exosomes derived from cancer‑associated fibroblasts to inhibit 5‑FU sensitivity by targeting NCALD in colorectal cancer". International Journal of Oncology 60.2 (2022): 14.
Chicago
Pan, S., Deng, Y., Fu, J., Zhang, Y., Zhang, Z., Qin, X."N6‑methyladenosine upregulates miR‑181d‑5p in exosomes derived from cancer‑associated fibroblasts to inhibit 5‑FU sensitivity by targeting NCALD in colorectal cancer". International Journal of Oncology 60, no. 2 (2022): 14. https://doi.org/10.3892/ijo.2022.5304