J Cancer 2019; 10(24):6003-6013. doi:10.7150/jca.35097

Research Paper

Long non-coding RNA LOC554202 promotes acquired gefitinib resistance in non-small cell lung cancer through upregulating miR-31 expression

Jing He1*, Shidai Jin1*, Wei Zhang2*, Deqin Wu3, Jun Li1, Jing Xu1✉, Wen Gao1✉

1. Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China
2. Department of Radiology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China
3. Department of Pharmacy, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China
*These authors contributed equally to this work

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Citation:
He J, Jin S, Zhang W, Wu D, Li J, Xu J, Gao W. Long non-coding RNA LOC554202 promotes acquired gefitinib resistance in non-small cell lung cancer through upregulating miR-31 expression. J Cancer 2019; 10(24):6003-6013. doi:10.7150/jca.35097. Available from http://www.jcancer.org/v10p6003.htm

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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.

Keywords: non-small-cell lung cancer, resistance, gefitinib, LOC554202, miR-31, proliferation, RAF-MEK-ERK, PI3K-AKT