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Original Article
- Lung and Thoracic cancer
- miR-4487 Enhances Gefitinib-Mediated Ubiquitination and Autophagic Degradation of EGFR in Non-Small Cell Lung Cancer Cells by Targeting USP37
- Mi Seong Kim, So Hui Kim, Sei Hoon Yang, Min Seuk Kim
- Cancer Res Treat. 2022;54(2):445-457. Published online August 3, 2021
- DOI: https://doi.org/10.4143/crt.2021.622
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Abstract
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ePub - Purpose
With the identification of epidermal growth factor receptor (EGFR) mutations in non–small cell lung cancer (NSCLC) cells, EGFR–tyrosine kinase inhibitors (TKIs) are being used widely as the first-line of treatment in NSCLC. These inhibitors block auto-phosphorylation of activated EGFR by competing with ATP binding and mediate EGFR degradation independent of exogenous epidermal growth factor, which is associated with the mutation variants of EGFR. However, the precise mechanisms underlying the TKI-mediated EGFR degradation are still unclear.
Materials and Methods
To examine the physiological roles of miR-4487 and ubiquitin-specific peptidase 37 (USP37) in gefitinib-mediated EGFR degradation in NSCLC cells, multiple NSCLC cell lines were applied. The level of EGFR expression, apoptosis marker and autophagic flux were determined by western blot. Expression level of miR-4487 and cell cycle arrest was analyzed by TaqMan assay and flow cytometry respectively.
Results
We found that gefitinib mediates EGFR degradation under normal culture conditions, and is dependent on autophagic flux and the mutation variants of EGFR. Gefitinib reduced expression levels of USP37, which mediated EGFR degradation similar to gefitinib. Our results also showed a gefitinib-mediated increase in endogenous miR-4487 level and presented evidence for the direct targeting of USP37 by miR-4487, resulting in the sequential enhancement of ubiquitination, autophagy, and EGFR degradation. Thus, the depletion of USP37 and overexpression of miR-4487 led to an increase in gefitinib-mediated apoptotic cell death.
Conclusion
These data suggest that miR-4487 is a potential target for treating NSCLC, and miR-4487/USP37-regulated EGFR degradation is a determinant for developing gefitinib resistance. -
Citations
Citations to this article as recorded by
- The significance of the crosstalk between ubiquitination or deubiquitination and ncRNAs in non-small cell lung cancer
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Frontiers in Oncology.2023;[Epub] CrossRef - Lung adenocarcinoma cell-derived exosomes promote M2 macrophage polarization through transmission of miR-3153 to activate the JNK signaling pathway
L Xu, L Wang, R Yang, T Li, X Zhu
Human Molecular Genetics.2023; 32(13): 2162. CrossRef - The potential role of miRNAs in the pathogenesis of salivary gland cancer – A Focus on signaling pathways interplay
Ahmed I. Abulsoud, Shereen Saeid Elshaer, Ahmed A. El-Husseiny, Doaa Fathi, Nourhan M. Abdelmaksoud, Sherif S. Abdel Mageed, Aya Salman, Mohamed Bakr Zaki, Hesham A. El-Mahdy, Ahmed Ismail, Elsayed G.E. Elsakka, Mai A. Abd-Elmawla, Hussein M. El-Husseiny,
Pathology - Research and Practice.2023; 247: 154584. CrossRef
- The significance of the crosstalk between ubiquitination or deubiquitination and ncRNAs in non-small cell lung cancer
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