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Revealing the underlying regulatory mechanism of LINC00313 in Osimertinib-resistant NSCLC cells by ceRNA network analysis

ABSTRACT: In this study, RNA-sequencing technology was employed to identify the differentially expressed lncRNAs (DE-lncRNAs) and mRNAs (DE-mRNAs) between H1975 and H1975OR. Based on the starbase 2.0 database, the potential targeting relationships between DE-lncRNAs and DE-mRNAs were predicted and identified to construct the ceRNA networks. Subsequently, functional and pathway enrichment analysis were carried for target DE-mRNAs to obtain functional pathways associated with Osimertinib resistance and potential drug resistance-related DE-mRNAs. Besides, the expression of LINC00313 and COL1A1 was validated by q-Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR). Finally, the activation of PI3K/Akt pathway was proved by immunohistochemistry staining.

ORGANISM(S): Homo sapiens

PROVIDER: GSE228049 | GEO | 2023/03/31

REPOSITORIES: GEO

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Project description:BackgroundOsimertinib, 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.MethodsRNA-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.ResultsFunctional 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.ConclusionsOur 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.

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Revealing the underlying regulatory mechanism of LINC00313 in Osimertinib-resistant NSCLC cells by ceRNA network analysis

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