Abstract:
:Non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation inevitably have a relapse due to the occurrence of acquired resistance, resulting in treatment failure. However, little is known about the mechanisms of acquired resistance of NSCLC patients. Here, we elucidated the expression pattern of LOC554202 and miR-31, and their biological functions and mechanisms in NSCLC with acquired EGFR TKI resistance to gefitinib. In the present study, we observed that LOC554202 and miR-31 promoted proliferation and clonogenic growth of gefitinib-resistant NSCLC cells in vitro. LOC554202 upregulated miR-31 expression and they both reduced sensitivity of NSCLC cells to gefitinib. In a xenograft mice model, we found that knockdown of miR-31 significantly repressed gefitinib-resistant NSCLC cells growth in vivo. Furthermore, both LOC554202 and miR-31 levels were significantly increased in NSCLC patients acquiring resistance to gefitinib, and the expression of LOC554202 was positively correlated with the expression of miR-31. By luciferase reporter assays, we identified RAS P21 Protein Activator 1 (RASA1) and Hypoxia Inducible Factor 1 Subunit Alpha Inhibitor (FIH-1) as direct targets of miR-31 in NSCLC cells. Mechanistically, miR-31 directly repressed RASA1 and FIH-1 expression, and thus, at least partially activated the RAF-MEK-ERK and PI3K-AKT signaling pathways in NSCLC with acquired resistance to gefitinib. In conclusion, these data will help us develop potential therapeutic targets for the diagnosis and treatment of acquired EGFR TKI resistance in EGFR-mutant NSCLC.
journal_name
J Cancerjournal_title
Journal of Cancerauthors
He J,Jin S,Zhang W,Wu D,Li J,Xu J,Gao Wdoi
10.7150/jca.35097subject
Has Abstractpub_date
2019-10-15 00:00:00pages
6003-6013issue
24issn
1837-9664pii
jcav10p6003journal_volume
10pub_type
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journal_title:Journal of Cancer
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journal_title:Journal of Cancer
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doi:10.7150/jca.22318
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更新日期:2018-08-06 00:00:00
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更新日期:2015-01-22 00:00:00
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doi:10.7150/jca.7668
更新日期:2014-01-23 00:00:00
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journal_title:Journal of Cancer
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