Long Noncoding RNA LINC00460 Promotes the Gefitinib Resistance of Nonsmall Cell Lung Cancer Through Epidermal Growth Factor Receptor by Sponging miR-769-5p.

Guodong Ma,Yan Yang,Jiping Zhu,Feng Liu

doi:10.1089/dna.2018.4462

Abstract

The vital roles of long noncoding RNAs (lncRNAs) in the nonsmall cell lung cancer (NSCLC) tumorigenesis are increasingly important. This work aims to investigate the role of lncRNA LINC00460 in the gefitinib resistance of NSCLC cells and discover its relevant mechanism. Our finding reveals that the expression of lncRNA LINC00460 is upregulated in the gefitinib-resistant NSCLC tissue and cells, and closely correlated with advanced tumor stage and clinical poor prognosis outcome. Gain and loss functional assays are performed in gefitinib-resistant NSCLC cells (A549/GR), stating that LINC00460 facilitates the 50% inhibitive concentration of gefitinib for NSCLC cells, multidrug-resistant-related proteins (P-gp, MRP1, and BCRP), as well as the invasion. In vivo, LINC00460 silencing represses the tumor growth. Bioinformatics prediction tools and luciferase analysis confirm that the upregulated LINC00460 sponged miR-769-5p in NSCLC cells; moreover, epidermal growth factor receptor (EGFR) is identified as a direct target gene of miR-769-5p. Verification experiments confirm that the restoration of EGFR could weaken the sensibility of NSCLC cells toward the gefitinib. In conclusion, our result demonstrates that LINC00460 plays a pivotal role in gefitinib resistance of NSCLC cells by targeting EGFR through sponging miR-769-5p. This finding might serve as a therapeutic target for NSCLC.

Highlights

Nonsmall cell lung cancer (NSCLC) is one of the most common types of human cancers that cause large number of cancer-related deaths worldwide, accounting for 85% of all lung cancer (Hisakane et al, 2017; Guo et al, 2018; Shen et al, 2018; Wu et al, 2018)
In the NSCLC patients who were diagnosed with gefitinib resistance, long noncoding RNAs (lncRNAs) LINC00460 expression was upregulated compared with those who were sensitive to the gefitinib chemotherapy (Fig. 1B)
Survival analysis revealed that these NSCLC who accompanied by high LINC00460 expression had unfavorable prognosis than the lower individuals (Fig. 1E)

Summary

Introduction

Nonsmall cell lung cancer (NSCLC) is one of the most common types of human cancers that cause large number of cancer-related deaths worldwide, accounting for 85% of all lung cancer (Hisakane et al, 2017; Guo et al, 2018; Shen et al, 2018; Wu et al, 2018). For a subtype of NSCLC patients who are marked with epidermal growth factor receptor (EGFR)-sensitive mutations, EGFR tyrosine kinase inhibitors (EGFR-TKIs) are developed to resist epithelial-derived solid tumor, such as gefitinib for advanced NSCLC (Peng et al, 2016; Jiang et al, 2017b; Li et al, 2017). The acquired drug resistance toward EGFR-TKIs appears with high frequency and leads to a limitation of gefitinib in the clinical treatment ( Jiang et al, 2017a). Noncoding RNAs (ncRNAs) are groups of transcripts without the protein-coding potential (Hu et al, 2017). NcRNAs contain two categories: long noncoding RNAs (lncRNAs) with >200 nucleotides and microRNAs (miRNAs) with 20–23 nucleotides (Zhu et al, 2017). In the NSCLC, the LINC00339 promoted the progression through FOXM1 by targeting miR-145, showing the important role of the LINC00339/miR-145/FOXM1 axis in the NSCLC tumorigenesis (Yuan et al, 2018)

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