Open Access

METTL3 antagonizes 5‑FU chemotherapy and confers drug resistance in colorectal carcinoma

  • Authors:
    • Min Li
    • Mingyue Xia
    • Ziyu Zhang
    • Yanyin Tan
    • Enjie Li
    • Zhigang Guo
    • Mingzhi Fang
    • Yong Zhu
    • Zhigang Hu
  • View Affiliations

  • Published online on: July 19, 2022     https://doi.org/10.3892/ijo.2022.5396
  • Article Number: 106
  • Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Colorectal cancer (CRC) is one of top five leading causes of cancer‑associated mortalities worldwide. 5‑Fluorouracil (5‑FU) is the first‑line chemotherapeutic drug in the treatment of CRC; however, its antineoplastic efficiency is limited due to acquired drug resistance. The regulatory mechanism underlying 5‑FU chemotherapeutic response and drug resistance in CRC remains largely unknown. The present study identified that silencing of methyltransferase‑like 3 (METTL3) suppressed the proliferation and migration of CRC HCT‑8 cells. Using cell survival assays, flow cytometric and colony formation analyses, it was revealed that inhibition of METTL3 sensitized HCT‑8 cells to 5‑FU by enhancing DNA damage and inducing apoptosis in HCT‑8 cells under 5‑FU treatment. Furthermore, the expression of METTL3 was upregulated in 5‑FU‑resistant CRC cells (HCT‑8R), which contributed to drug resistance through regulation of RAD51 associated Protein 1 (RAD51AP1) expression. Western blotting, immunofluorescence staining and drug sensitivity assays demonstrated that knockdown of METTL3 augmented 5‑FU‑induced DNA damage and overcame 5‑FU‑resistance in HCT‑8R cells, which could be mimicked by inhibition of RAD51AP1. The present study revealed that the METTL3/RAD51AP1 axis plays an important role in the acquisition of 5‑FU resistance in CRC, and targeting METTL3/RAD51AP1 may be a promising adjuvant therapeutic strategy for patients with CRC, particularly for those with 5‑FU‑resistant CRC.

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September-2022
Volume 61 Issue 3

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Copy and paste a formatted citation
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Spandidos Publications style
Li M, Xia M, Zhang Z, Tan Y, Li E, Guo Z, Fang M, Zhu Y and Hu Z: METTL3 antagonizes 5‑FU chemotherapy and confers drug resistance in colorectal carcinoma. Int J Oncol 61: 106, 2022
APA
Li, M., Xia, M., Zhang, Z., Tan, Y., Li, E., Guo, Z. ... Hu, Z. (2022). METTL3 antagonizes 5‑FU chemotherapy and confers drug resistance in colorectal carcinoma. International Journal of Oncology, 61, 106. https://doi.org/10.3892/ijo.2022.5396
MLA
Li, M., Xia, M., Zhang, Z., Tan, Y., Li, E., Guo, Z., Fang, M., Zhu, Y., Hu, Z."METTL3 antagonizes 5‑FU chemotherapy and confers drug resistance in colorectal carcinoma". International Journal of Oncology 61.3 (2022): 106.
Chicago
Li, M., Xia, M., Zhang, Z., Tan, Y., Li, E., Guo, Z., Fang, M., Zhu, Y., Hu, Z."METTL3 antagonizes 5‑FU chemotherapy and confers drug resistance in colorectal carcinoma". International Journal of Oncology 61, no. 3 (2022): 106. https://doi.org/10.3892/ijo.2022.5396