Silencing of Long Non-coding RNA MIAT Sensitizes Lung Cancer Cells to Gefitinib by Epigenetically Regulating miR-34a.

Yunfeng Fu,Lian Li,Rong Gui,Yanwei Luo,Chengyuan Li,Jing Liu

doi:10.3389/fphar.2018.00082

Abstract

Long non-coding RNA (lncRNA) myocardial infarction associated transcript (MIAT) was recently identified as oncogene in several cancers. However, the role of MIAT on acquired resistance in lung cancer and the underlying mechanisms remain unclear. Here, we showed that the expression of MIAT in lung cancer tissues was upregulated compared with adjacent tissues. LncRNA MIAT expression was associated with tumor size, lymph node metastasis, distant metastasis and TNM stage. Univariate analysis and multivariate analysis revealed that the lncRNA MIAT to be an independent factor for predicating the prognosis of lung cancer patients. Low lncRNA MIAT have longer overall survival time and progression-free survival time than patients with high lncRNA MIAT expression. Moreover, the knockdown of MIAT significantly sensitized PC9 and gefitinib-resistant PC9 cells to gefitinib in vitro and in vivo, and increased the expression of miR-34a and inactivated PI3K/Akt signaling. MIAT interacted with miR-34a and epigenetically controlled the miR-34a expression by hyper-methylating its promotor. Taken together, our findings demonstrated that knockdown of MIAT by siRNA enhances lung cancer cells to gefitinib through the PI3K/Akt signaling pathway by epigenetically regulating miR-34a. Thus, MIAT may be a useful prognostic marker and therapeutic target for lung cancer patients.

Highlights

Lung cancer, including small-cell lung cancer (SCLC, accounting for about 20%) and non-smallcell lung cancer (NSCLC, accounting for about 80%), is a leading cause of cancer deaths worldwide
We found that Long non-coding RNA (lncRNA) myocardial infarction associated transcript (MIAT) was significantly increased in lung cancer tissues compared with adjacent control (Figure 1A)
We divided the patients into two groups according to the median of lncRNA MIAT and found that lncRNA MIAT expression was associated with tumor size (p = 0.005), lymph node metastasis (p = 0.007), distant metastasis (p = 0.006) and TNM stage (p = 0.003), but not associated with age (p = 0.481), gender (p = 0.560) and histology type (p = 0.193) (Table 1)

Summary

Introduction

Lung cancer, including small-cell lung cancer (SCLC, accounting for about 20%) and non-smallcell lung cancer (NSCLC, accounting for about 80%), is a leading cause of cancer deaths worldwide. Amount of genomic and epigenomic alterations have been revealed during the development of lung cancer (Ma et al, 2017). The NSCLC cases often harbor epidermal growth factor receptor (EGFR) activating mutation. EGFR-tyrosine kinase inhibitors (EGFR-TKIs) are the first line chemotherapy drugs for EGFR-mutant NSCLC patients. Acquired drug resistance often occurs on the continuous treatment (Zhang and Yuan, 2016). Once activated by ligands and receptor dimerization, EGFR can activate cellular signaling pathways such as the phosphoinositide 3-kinase (PI3K)-AKT pathway, leading to increased cell proliferation and survival. The mutations or genetic polymorphisms of EGFR may result in primary resistance on EGFR-TKIs, and gene copy

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