LncRNA BC promotes lung adenocarcinoma progression by modulating IMPAD1 alternative splicing.

Autor: Chen QW; Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, P. R. China.; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P. R. China., Cai QQ; Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai, P. R. China., Yang Y; Key Laboratory of Glycoconjugate Research Ministry of Public Health, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, P. R. China., Dong S; Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, P. R. China.; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P. R. China., Liu YY; Key Laboratory of Glycoconjugate Research Ministry of Public Health, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, P. R. China., Chen ZY; Key Laboratory of Glycoconjugate Research Ministry of Public Health, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, P. R. China., Kang CL; Key Laboratory of Glycoconjugate Research Ministry of Public Health, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, P. R. China., Qi B; Key Laboratory of Glycoconjugate Research Ministry of Public Health, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, P. R. China., Dong YW; Key Laboratory of Glycoconjugate Research Ministry of Public Health, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, P. R. China., Wu W; Department of Pathology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, P. R. China., Zhuang LP; Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, P. R. China.; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P. R. China., Shen YH; Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, P. R. China.; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P. R. China., Meng ZQ; Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, P. R. China.; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P. R. China., Wu XZ; Key Laboratory of Glycoconjugate Research Ministry of Public Health, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, P. R. China.
Jazyk: angličtina
Zdroj: Clinical and translational medicine [Clin Transl Med] 2023 Jan; Vol. 13 (1), pp. e1129.
DOI: 10.1002/ctm2.1129
Abstrakt: Background: The therapeutic value of targeted therapies in patients with lung cancer is reduced when tumours acquire secondary resistance after an initial period of successful treatment. However, the molecular events behind the resistance to targeted therapies in lung cancer remain largely unknown.
Aims: To discover the important role and mechanism of lncRNA BC in promoting tumor metastasis and influencing clinical prognosis of LUAD.
Materials & Methods: Microarrays were used to screen a comprehensive set of lncRNAs with differential expression profiles in lung cancer cells. The functional role and mechanism of lncRNA were further investigated by gain- and loss-of-function assays. RNA pull-down, protein assays, and mass spectrometry were used to identify proteins that interacted with lncRNA. TaqMan PCR was used to measure lncRNA in lung adenocarcinoma and adjacent nontumor tissues from 428 patients. The clinical significance of lncRNA identified was statistically confirmed in this cohort of patients.
Results: In this study, we show that the long non-coding RNA BC009639 (BC) is involved in acquired resistance to EGFR-targeted therapies. Among the 235 long non-coding RNAs that were differentially expressed in lung cancer cell lines, with different metastatic potentials, BC promoted growth, invasion, metastasis, and resistance to EGFR-tyrosine kinase inhibitors (EGFR-TKIs), both in vitro and in vivo. BC was highly expressed in 428 patients with lung adenocarcinoma (LUAD) and high BC expression correlated with reduced efficacy of EGFR-TKI therapy. To uncover the molecular mechanism of BC-mediated EGFR-TKI resistance in lung cancer, we screened and identified nucleolin and hnRNPK that interact with BC. BC formed the splicing complex with nucleolin and hnRNPK to facilitate the production of a non-protein-coding inositol monophosphatase domain containing 1 (IMPAD1) splice variant, instead of the protein-coding variant. The BC-mediated alternative splicing (AS) of IMPAD1 resulted in the induction of the epithelial-mesenchymal transition and resistance to EGFR-TKI in lung cancer. High BC expression correlated with clinical progress and poor survival among 402 patients with LUAD.
Disscussion: Through alternative splicing, BC boosted the non-coding IMPAD1-203 transcript variant while suppressing the IMPAD1-201 variant. In order to control the processing of pre-mRNA, BC not only attracted RNA binding proteins (NCL, IGF2BP1) or splicing factors (hnRNPK), but also controlled the formation of the splicing-regulator complex by creating RNA-RNA-duplexes.
Conclusion: Our results reveal an important role for BC in mediating resistance to EGFR-targeted therapy in LUAD through IMPAD1 AS and in implication for the targeted therapy resistance.
(© 2023 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)
Databáze: MEDLINE
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