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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 Therapy volume 29, pages 1686–1696 (2022)Cite this article

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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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Fig. 1: Lnc-ABCA12-8 is overexpressed in NSCLC with acquired resistance to gefitinib.
Fig. 2: Lnc-ABCA12-8 reduces gefitinib sensitivity in NSCLC cells.
Fig. 3: Lnc-ABCA12-8 physically interacts with ASF/SF2 in NSCLC cells.
Fig. 4: Lnc-ABCA12-8 regulates alternative splicing at IIICS region of FN1 through binding to ASF/SF2.
Fig. 5: The entire IIICS fragment of FN1 is involved in the impact of lnc-ABCA12-8 on the sensitivity of NSCLC cells to gefitinib.
Fig. 6: Lnc-ABCA12-8 promotes NSCLC cell proliferation and metastasis in vivo.

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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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Authors and Affiliations

  1. Institute of Life Sciences, Chongqing Medical University, 400016, Chongqing, PR China

    Shuai He, Jingjing Shi, HongHao Zhou, Qingling Li & Lanxiang Wu

  2. Molecular Medicine Diagnostic and Testing Center, Chongqing Medical University, Chongqing, PR China

    Shuai He, Qingling Li & Lanxiang Wu

  3. Pharmacogenetics Research Institute, Institute of Clinical Pharmacology, Central South University, Changsha, PR China

    HongHao Zhou

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Contributions

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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Correspondence to Qingling Li or Lanxiang Wu.

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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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