Additionally, lncRNA SNHG20 promoted proliferation and migration by epigenetically silencing P21 8. For example, one study showed that LINC01234 activated VAV3 at the post-transcription level and repressed BTG2 at the transcription level, which subsequently led to epithelial–to–mesenchymal transition in NSCLC cells. Therefore, in-depth study of the mechanism of drug resistance to EGFR-TKIs, the search for genes related to drug resistance, and the exploration of ways to reverse drug resistance have recently become important topics in lung cancer treatment research.Īs one type of non-coding RNA, long-chain non-coding RNA (lncRNA) can regulate gene expression on multiple levels, such as the epigenetic, transcription, and post-transcription levels 5, 6, 7. However, acquired resistance is inevitable with gefitinib, which leads to treatment failure 4. The first generation of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI), represented by gefitinib, could significantly prolong the median survival of patients with advanced lung cancer with EGFR-sensitive mutations and greatly improve their quality of life 3. Despite continuous developments and progress in therapeutic measures, such as surgery, radiotherapy, and drug therapy (including chemotherapy, targeted therapy, and immunotherapy), the prognosis of patients with advanced NSCLC is still poor 1, 2.
Non-small cell lung cancer (NSCLC) is one of the most common malignant tumors worldwide. Our results highlight the essential role of CASC9 in gefitinib resistance, suggesting that the CASC9/EZH2/DUSP1 axis might be a novel target for overcoming EGFR-TKI resistance in NSCLC. Furthermore, ectopic expression of DUSP1 increased gefitinib sensitivity by inactivating the ERK pathway. Mechanistically, CASC9 repressed the tumor suppressor DUSP1 by recruiting histone methyltransferase EZH2, thereby increasing the resistance to gefitinib. Gain and loss of function studies showed that CASC9 inhibition restored gefitinib sensitivity both in vitro and in vivo, whereas CASC9 overexpression promoted gefitinib resistance.
In this study, by analyzing the differentially expressed lncRNAs in gefitinib-resistant cells and gefitinib-sensitive cells in the National Institute of Health GEO dataset, we found that lncRNA CASC9 expression was upregulated, and this was also verified in resistant tissues. The long noncoding RNAs (lncRNAs) are known to regulate tumorigenesis and cancer progression, but their contributions to NSCLC gefitinib resistance remain poorly understood. Resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib, has greatly affected clinical outcomes in non-small cell lung cancer (NSCLC) patients.
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