Revealing underlying regulatory mechanisms of LINC00313 in Osimertinib-resistant LUAD cells by ceRNA network analysis

• Published in: Translational oncology Vol. 43; p. 101895
• Main Authors: Ding, Dandan, Xu, Chenguang, Zhang, Jufeng, Zhang, Ying, Xue, Lipeng, Song, Jingjing, Luo, Zhiming, Hong, Xiaoyu, Wang, Jian, Liang, Weicheng, Xue, Xingyang
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2024; Elsevier
• Subjects: EGFR-TKIs; LINC00313; lncRNA-miRNA-mRNA (ceRNA); Lung adenocarcinoma (LUAD); Osimertinib resistance; EGFR-TKIs; Osimertinib resistance; Lung adenocarcinoma (LUAD); lncRNA-miRNA-mRNA (ceRNA); LINC00313
• ISSN: 1936-5233; 1936-5233
• DOI: 10.1016/j.tranon.2024.101895

•The LINC00313/miR-218-5p/COL1A1 axis is proposed as a ceRNA regulatory mechanism that contributes to the development of acquired resistance to osimertinib in LUAD via the PI3K/Akt pathway.•Some newly identified target DE-mRNAs, regulated by LINC00313, function as potential risk signatures for predicting the prognosis of LUAD.•High expression levels of both LINC00313 and COL1A1 are significantly associated with a poorer prognosis in LUAD. Osimertinib, a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), is the preferred treatment for EGFR-mutated lung cancer. However, acquired resistance inevitably develops. While non-coding RNAs have been implicated in lung cancer through various functions, the molecular mechanisms responsible for osimertinib resistance remain incompletely elucidated. RNA-sequencing technology was employed to determine differentially expressed lncRNAs (DE-lncRNAs) and mRNAs (DE-mRNAs) between H1975 and H1975OR cell lines. Starbase 2.0 was utilized to predict DE-lncRNA and DE-mRNA interactions, constructing ceRNA networks. Subsequently, functional and pathway enrichment analysis were performed on target DE-mRNAs to identify pathways associated with osimertinib resistance. Key target DE-mRNAs were then selected as potential risk signatures for lung adenocarcinoma (LUAD) prognostic modeling using multivariate Cox regression analyses. The Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) and immunohistochemistry staining were used for result validation. Functional analysis revealed that the identified DE-mRNAs primarily enriched in EGFR-TKI resistance pathways, especially in the PI3K/Akt signaling pathway, where their concerted actions may lead to osimertinib resistance. Specifically, upregulation of LINC00313 enhanced COL1A1 expression by acting as a miR-218-5p sponge, triggering an upstream response that activates the PI3K/Akt pathway, potentially contributing to osimertinib resistance. Furthermore, the expressions of LINC00313 and COL1A1 were validated by qRT-PCR, and the activation of the PI3K/Akt pathway was confirmed by immunohistochemistry staining. Our results suggest that the LINC00313/miR-218-5p/COL1A1 axis potentially contributes to osimertinib resistance through the PI3K/Akt signaling pathway, providing novel insights into the molecular mechanisms underlying acquired osimertinib resistance in LUAD. Additionally, our study may aid in the identification of potential therapeutic targets for overcoming resistance to osimertinib.