Increased MIR31HG lncRNA expression increases gefitinib resistance in non-small cell lung cancer cell lines through the EGFR/PI3K/AKT signaling pathway

Abstract

The aim of the present study was to gain insight into the molecular mechanism of gefitinib resistance in non-small cell lung cancer (NSCLC), and demonstrate whether long noncoding RNA (lncRNA) expression signatures differ between gefitinib-sensitive PC9 and gefitinib-resistant PC9 (PC9-R) cell lines. PC9 and PC9-R cells were treated with gefitinib and, after 48 h, proliferation and apoptosis were analyzed using a Cell Counting Kit-8 (CCK-8) assay and flow cytometry. Microarray expression profiling of lncRNAs was undertaken in both PC9 and PC9-R cells, and the expression profiles were verified by reverse transcription quantitative-polymerase chain reaction. The EGFR/PI3K/AKT signaling pathway and mitochondrial apoptosis protein expression levels were assessed by western blot analysis. The PC9 cell line treated with gefitinib had a more significant effect on cell viability and apoptosis than the PC9-R cell line (P<0.05). Expression of various lncRNAs differed significantly between the two cell lines, and MIR31HG expression in particular was significantly higher in PC9-R cells. As expected, MIR31HG lncRNA knockdown sensitized PC9-R cells to gefitinib, and further experiments revealed that turning off the EGFR/PI3K/AKT signaling pathway activated expression of p53 in PC9-R cells transfected with si-MIR31HG. Furthermore, PC9-R cells transfected with si-MIR31HG induced cell apoptosis through the mitochondrial apoptosis pathway, and arrested the cell cycle in the G0/G1 phase. The results of the current study suggest that MIR31HG lncRNA levels in PC9-R cells are higher than in PC9 cells. Furthermore, overexpression of MIR31HG lncRNAs may contribute to gefitinib resistance in PC9-R cells through the EGFR/PI3K/AKT pathway, which impacts on cell proliferation, apoptosis and the cell cycle. MIR31HG lncRNA may therefore be a novel candidate biomarker for future therapeutic strategies involving EGFR-TKIs.

Long non‐coding RNA LINC00968 acts as oncogene in NSCLC by activating the Wnt signaling pathway

“…For example, in clear cell renal cell carcinoma, lncRNA MRCCAT1 can induce tumor metastasis through inhibiting NPR3 and activating p38‐MAPK signaling (Li et al, ). Upregulation of lncRNA MIR31HG expression promotes gefitinib resistance in NSCLC cell lines by activating EGFR/PI3K/AKT signaling pathway (Wang, Jiang, et al, ). In lung cancer, microRNA‐449a can inhibit cell growth by regulating lncRNA NEAT1 (You et al, ).…”

Role of long non‐coding RNA in drug resistance in non‐small cell lung cancer

“…Wang et al . revealed that overexpression of MIR31HG lncRNA contributes to gefitinib resistance in NSCLC cell lines, affecting cell proliferation, apoptosis, and the cell cycle by activating the EGFR/PI3K/AKT pathway …”

“…71 Wang et al revealed that overexpression of MIR31HG lncRNA contributes to gefitinib resistance in NSCLC cell lines, affecting cell proliferation, apoptosis, and the cell cycle by activating the EGFR/PI3K/AKT pathway. 72 LncRNA UCA1 was first identified in bladder cancer cells and is involved in the invasion and progression of bladder cancer. 73 In lung cancer, overexpression of UCA1 induces non-T790M acquired resistance to EGFR-TKIs by activating the AKT/mTOR pathway.…”

Long non‐coding RNAs: How to regulate the metastasis of non–small‐cell lung cancer

“…MIR31HG was a LncRNA, identified as >2166 nucleotides in length . Recent studies showed that increased MIR31HG expression increased gefitinib resistance in NSCLC lines through the EGFR/PI3K/AKT signalling pathway . Zheng et al also discovered MIR31HG could promote the invasion of NSCLC by activating the Wnt/β‐catenin signalling pathway …”