CircSETD3 mediates acquired resistance to gefitinib in non-small lung cancer cells by FXR1/ECT2 pathway

• Published in: The international journal of biochemistry & cell biology 2023-01, Vol.154, p.106344-106344, Article 106344
• Main Authors: Wen, Chunjie, Li, Yaji, Huang, Yutang, Wang, Nan, He, Shuai, Bao, Meihua, Zhou, Honghao, Wu, Lanxiang
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - pathology; Cell Line, Tumor; Cell Proliferation; circSETD3; Drug Resistance, Neoplasm - genetics; Epithelial Cells - metabolism; ErbB Receptors - genetics; FXR1; Gefitinib - pharmacology; Gefitinib - therapeutic use; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Mice; Non-small cell lung cancer; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins - metabolism; Resistance; RNA, Circular - genetics; RNA-Binding Proteins - genetics
• ISSN: 1357-2725; 1878-5875
• DOI: 10.1016/j.biocel.2022.106344

Gefitinib is the first-line treatment for non-small cell lung cancer (NSCLC) harboring EGFR sensitive mutation. However, acquired resistance significantly limits its therapeutic efficacy. CircSETD3 has been reported to promote gefitinib resistance in NSCLC cells, however, its underlying mechanisms have not been fully clarified. The expression of circSETD3 were detected in NSCLC patients who received gefitinib as first-line treatment, including 20 gefitinib-sensitive patients and 20 acquired gefitinib-resistant patients. Cell viability were examined by CCK8 assay. The mRNA and protein levels were detected by qRT-PCR and western blot. Using RNA pull-down assay followed by mass spectrometry to identified proteins that interact with circSETD3. The interaction between circSETD3 and fragile X-related protein-1 (FXR1) were further validated by RNA immunoprecipitation (RIP) and pull-down analysis. Fuorescence in situ hybridization (FISH) and immunofluorescence (IF) assays was used for the identification of sub-location of circSETD3 and FXR1 in cells. The effect of circSETD3 overexpression and knockdown on NSCLC tumor growth to gefitinib sensitivity was detected using the mouse xenograft model. CircSETD3 was significantly upregulated in gefitinib-resistant NSCLC cells, and decreased the gefitinib sensitivity in vitro and in vivo. Mechanically, circSETD3 facilitated FXR1 binding to its downstream mRNA target, epithelial cell-transforming sequence 2 (ECT2), promoting ECT2 mRNA decay, which further inhibited cellular apoptosis. CircSETD3/FXR1/ECT2 axis plays a critical role in the acquired resistance to gefitinib in NSCLC. Our results highlight the potential of circSETD3 as a biomarker and therapeutic target for NSCLC patients with acquired gefitinib resistance.