Abstract
Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib, has dramatically impaired the clinical outcomes in non-small cell lung cancer (NSCLC) patients, but the mechanisms are still unclear in substantial cases. In our previous study, we demonstrated that a novel long non-coding RNA (lncRNA), lnc-ABCA12-8, was overexpressed in gefitinib-resistant NSCLC cells, but the exact function is unknown. In this study, we confirmed that lnc-ABCA12-8 was significantly upregulated both in NSCLC cell lines and the plasma samples of NSCLC patients with acquired resistance to gefitinib. Downregulation of lnc-ABCA12-8 could reverse gefitinib resistance both in vitro and in vivo. Mechanistically, lnc-ABCA12-8 interacted with alternative splicing factor/splicing factor 2 (ASF/SF2), promoted the binding of ASF/SF2 to the IIICS exon of fibronectin 1 (FN1) gene and enhanced the IIICS region inclusion during fibronectin 1 (FN1) alternative splicing, resulting in the upregulation of entire IIICS region, and enhanced cell proliferation, migration, invasion, and adhesion. Taken together, our study suggest that lnc-ABCA12-8 is involved in the acquired resistance to gefitinib, and may be a novel biomarker and therapeutic target for monitoring and overcoming gefitinib resistance in NSCLC.
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Data availability
The data that support the findings of this study are available on request from the corresponding author.
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Funding
This work was supported by the Natural Science Foundation of China (No. 82073938), Chongqing Municipal Education Commission (No. KJQN201900424), Program for Youth Innovation in Future Medicine, Chongqing Medical University (No.W0093), the Natural Science Foundation of Chongqing (No. cstc2020jcyj-msxmX0246), Scientific and Technological Research Program of and Scientific and Technological Research Program of Yuzhong District, Chongqing (No. 20200102).
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S.H. performed and analyzed most of the experiments. J.S. assisted with data analysis. L.W. and Q.L. wrote the manuscript. L.W. provided financial support and critical intellectual input in the study design and manuscript preparation. L.W. and H.Z. revised the paper. All authors discussed the results and commented on the manuscript. All authors read and approved the final manuscript.
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He, S., Shi, J., Zhou, H. et al. Lnc-ABCA12-8 confers acquired resistance to gefitinib in non-small cell lung cancer by regulating the alternative splicing of fibronectin 1 in the IIICS region. Cancer Gene Ther 29, 1686–1696 (2022). https://doi.org/10.1038/s41417-022-00483-0
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DOI: https://doi.org/10.1038/s41417-022-00483-0