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LINC01559 drives osimertinib resistance in NSCLC through a ceRNA network regulating miR-320a/IGF2BP3 axis
Leidi Xu1, Yibo Zhang1, Liangliang Xing1
1Department of Pulmonary and Critical Care Medicine, Xijing Hospital, Air-Force Medical University, Xi'an, China.
Background:
Osimertinib resistance remains a major challenge in the treatment of lung adenocarcinoma. Long non-coding RNAs (lncRNAs) have emerged as key regulators of drug resistance, but their roles in osimertinib resistance are poorly understood. This study aimed to identify lncRNAs driving osimertinib resistance and elucidate their molecular mechanisms.
Methods:
Multi-cohort analysis (GSE222820, GSE232890, GSE255958) identified osimertinib resistance-associated lncRNAs. Functional validation employed in vitro assays (proliferation, migration, invasion, drug sensitivity) and xenograft models. Mechanistic studies involved luciferase reporter assays, RNA immunoprecipitation (RIP), and Western blotting. Clinical correlations were analyzed using TCGA-LUAD data.
Results:
Our findings demonstrated that LINC01559 was markedly upregulated in LUAD tissues and osimertinib-resistant cell lines, correlating with poor patient survival. Functional analyses revealed that LINC01559 critically regulates processes linked to drug resistance, enhancing tumor cell proliferation, migration, and invasive capabilities. Knockdown of LINC01559 sensitized resistant cells to osimertinib, significantly reducing colony-forming potential and suppressing migratory/invasive behaviors. In contrast, overexpression of LINC01559 exacerbated therapeutic resistance. Mechanistically, LINC01559 functions as a competing endogenous RNA (ceRNA) by sponging miR-320a, promote osimertinib -resistance and upregulate the expression of the miR-320a target IGF2BP3. Rescue experiments and xenograft models confirmed that Linc01559 drives resistance via the miR-320a/IGF2BP3 axis.
Conclusion:
This study identifies LINC01559 as a novel ceRNA that drives osimertinib resistance in lung adenocarcinoma by sponging miR-320a to enhance IGF2BP3 expression. Targeting the LINC01559/miR-320a/IGF2BP3 axis may provide a therapeutic strategy to overcome osimertinib resistance.
Insights
Osimertinib resistance in lung adenocarcinoma is driven by LINC01559, a long non-coding RNA. Targeting the LINC01559/miR-320a/IGF2BP3 pathway offers a potential strategy to overcome drug resistance.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Osimertinib resistance is a significant clinical challenge in lung adenocarcinoma treatment.
- Long non-coding RNAs (lncRNAs) are implicated in drug resistance, but their specific roles in osimertinib resistance are not well understood.
- Identifying novel molecular mechanisms driving osimertinib resistance is crucial for developing effective therapeutic strategies.
Purpose of the Study:
- To identify lncRNAs associated with osimertinib resistance in lung adenocarcinoma.
- To elucidate the molecular mechanisms by which identified lncRNAs contribute to osimertinib resistance.
- To explore the potential of targeting these lncRNAs as a therapeutic approach.
Main Methods:
- Multi-cohort genomic data analysis to identify resistance-associated lncRNAs.
- In vitro functional assays (proliferation, migration, invasion, drug sensitivity) and xenograft models for validation.
- Mechanistic investigations including luciferase reporter assays, RNA immunoprecipitation (RIP), and Western blotting.
- Analysis of clinical data from The Cancer Genome Atlas (TCGA) for correlation studies.
Main Results:
- LINC01559 was significantly upregulated in lung adenocarcinoma tissues and osimertinib-resistant cells, correlating with poorer patient survival.
- LINC01559 knockdown resensitized resistant cells to osimertinib, reducing proliferation, migration, and invasion.
- LINC01559 acts as a competing endogenous RNA (ceRNA) by sponging miR-320a, leading to increased expression of its target, IGF2BP3.
- The LINC01559/miR-320a/IGF2BP3 axis was confirmed to drive osimertinib resistance in xenograft models.
Conclusions:
- LINC01559 is identified as a novel ceRNA that promotes osimertinib resistance in lung adenocarcinoma.
- The mechanism involves LINC01559 sponging miR-320a, thereby upregulating IGF2BP3 expression.
- Targeting the LINC01559/miR-320a/IGF2BP3 axis presents a promising therapeutic strategy to overcome osimertinib resistance.
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