LncRNA BC promotes lung adenocarcinoma progression by modulating IMPAD1 alternative splicing

Author:

Chen Qi Wen12,Cai Qian Qian3ORCID,Yang Ying4,Dong Shu12,Liu Yuan Yuan4,Chen Zhong Yi4,Kang Chun Lan4,Qi Bing4,Dong Yi Wei4,Wu Wei5,Zhuang Li Ping12,Shen Ye Hua12,Meng Zhi Qiang12,Wu Xing Zhong4

Affiliation:

1. Department of Integrative Oncology Fudan University Shanghai Cancer Center Shanghai P. R. China

2. Department of Oncology, Shanghai Medical College Fudan University Shanghai P. R. China

3. Shanghai Key Laboratory of Molecular Imaging Shanghai University of Medicine and Health Sciences Shanghai P. R. China

4. 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

5. Department of Pathology Shanghai Pulmonary Hospital, Tongji University School of Medicine Shanghai P. R. China

Abstract

AbstractBackgroundThe 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.AimsTo 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.ResultsIn 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.DisscussionThrough 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.ConclusionOur 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.

Funder

National Natural Science Foundation of China

Publisher

Wiley

Subject

Molecular Medicine,Medicine (miscellaneous)

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