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

作者全名："Wen, Chunjie; Li, Yaji; Huang, Yutang; Wang, Nan; He, Shuai; Bao, Meihua; Zhou, Honghao; Wu, Lanxiang"

作者地址："[Wen, Chunjie; Li, Yaji; Huang, Yutang; Wang, Nan; He, Shuai; Zhou, Honghao; Wu, Lanxiang] Chongqing Med Univ, Inst Life Sci, Chongqing 400016, Peoples R China; [He, Shuai; Wu, Lanxiang] Chongqing Med Univ, Mol Med Diagnost & Testing Ctr, Chongqing, Peoples R China; [Bao, Meihua] Changsha Med Univ, Hunan Key Lab Res & Dev Novel Pharmaceut Preparat, Changsha 410219, Peoples R China; [Bao, Meihua] Changsha Med Univ, Academician Workstat, Changsha 410219, Peoples R China; [Zhou, Honghao] Cent South Univ, Pharmacogenet Res Inst, Inst Clin Pharmacol, Changsha 410078, Peoples R China"

通信作者："Wu, LX (通讯作者)，Chongqing Med Univ, Inst Life Sci, Chongqing 400016, Peoples R China."

来源：INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY

ESI学科分类：BIOLOGY & BIOCHEMISTRY

WOS号：WOS:000910170700001

JCR分区：Q2

影响因子：3.4

年份：2023

卷号：154

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：circSETD3; Non-small cell lung cancer; Resistance; FXR1

摘要："Background: 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.Methods: 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 immu-noprecipitation (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.Results: 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.Conclusion: 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 ac-quired gefitinib resistance."

基金机构："Natural Science Foundation of China [82073938, 82274023]; Natural Science Foundation of Chongqing [cstc2020jcyj-msxmX0246, cstc2020jcyj-msxmX0258]; Scientific and Technological Research Program of Yuzhong District, Chongqing [20200102]; Youth Innovation in Future Medicine, Chongqing Medical University [W0093]; Scientific and Technological Research Program of Chongqing Municipal Education Commission [KJQN202200432]"

基金资助正文："This work was supported by the Natural Science Foundation of China (No. 82073938, 82274023) , the Natural Science Foundation of Chongqing (No. cstc2020jcyj-msxmX0246, cstc2020jcyj-msxmX0258) , Scientific and Technological Research Program of Yuzhong District, Chongqing (No. 20200102) , Youth Innovation in Future Medicine, Chongqing Medical University (No. W0093) , the Scientific and Technological Research Program of Yuzhong District, Chongqing (No. 20200102) , and the Scientific and Technological Research Program of Chongqing Municipal Education Commission (No. KJQN202200432) ."