4.5 Article

MiR-133a-3p attenuates resistance of non-small cell lung cancer cells to gefitinib by targeting SPAG5

Journal

JOURNAL OF CLINICAL LABORATORY ANALYSIS
Volume 35, Issue 7, Pages -

Publisher

WILEY
DOI: 10.1002/jcla.23853

Keywords

gefitinib resistance; miR-133a-3p; NSCLC; signaling pathway; SPAG5

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The study revealed that miR-133a-3p was significantly downregulated in gefitinib-resistant NSCLC cells, and overexpression of miR-133a-3p could increase the sensitivity of cells to gefitinib. SPAG5 was identified as an important target gene of miR-133a-3p, which could reverse the miR-133a-3p-mediated gefitinib sensitivity.
Background: Gefitinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), clinically used to treat patients with non-small cell lung cancer driven by EGFR mutations. Unfortunately, EGFR-TKI resistance has become a clinical problem for the effective treatment of NSCLC patients. The purpose of this study was to explore the effect and mechanism of miR-133a-3p on the gefitinib sensitivity of NSCLC cells. Methods: The gefitinib-resistant PC9 (PC9/GR) cells were established through repeated long-term exposure to gefitinib for half a year. Then, PC9/GR cells were transfected with miR-133a-3p mimics and PC9 cells were transfected with miR-133a-3p inhibitors to increase or decrease the expression of miR-133a-3p. CCK-8 assay, colony formation assay, and caspase-3 activity assay were employed to detect cell resistance to gefitinib. Quantitative real-time PCR and Western blotting were used to evaluate the levels of miR-133a-3p, SPAG5, and other related genes. Starbase database was used to predict the target gene of miR-133a-3p and the prognosis of NSCLC patients. Target gene of miR-133a-3p was verified through dual-luciferase reporter gene assay. Results: MiR-133a-3p was significantly downregulated in gefitinib-resistant cell line PC9/GR vs. gefitinib-sensitive cell line PC9. Overexpression of miR-133a-3p increased the sensitivity of NSCLC cells to gefitinib and vice versa. Furthermore, SPAG5 is an important target gene of miR-133a-3p, and SPAG5 can reverse miR-133a-3p-mediated gefitinib sensitivity of NSCLC cells. Conclusions: These findings indicated that miR-133a-3p/SPAG5 axis played a vital role in acquired resistance to gefitinib in NSCLC cells, and miR-133a-3p may represent a potential therapeutic strategy for the treatment of human NSCLC.

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