MiR-101-3p sensitizes non-small cell lung cancer cells to irradiation

Zhonghui Li,Ying Wang,Meilin Qin,Zhenjie Qu,Hua Zhang

doi:10.1515/med-2020-0044

Abstract

Recent studies have revealed that microRNAs regulate radiosensitivity of non-small cell lung cancer (NSCLC). The aim of this study was to investigate whether miR-101-3p is correlated with radiosensitivity of NSCLC. According to our results, miR-101-3p was downregulated in NSCLC tissues and cell lines. Moreover, miR-101-3p was decreased in A549 cells’ response to irradiation in a dose-dependent manner. Upregulation of miR-101-3p decreased survival fraction and colony formation rate and increased irradiation-induced apoptosis in irradiation-resistant cells, while miR-101-3p depletion had the opposite effects in irradiation-sensitive cells. Furthermore, mechanistic target of rapamycin (mTOR) is a target gene of miR-101-3p. The expressions of mTOR, p-mTOR, and p-S6 were curbed by overexpression of miR-101-3p in A549R cells, which was enhanced by repression of miR-101-3p in A549 cells. Intriguingly, elevation in mTOR abated miR-101-3p upregulation-induced increase in irradiation sensitivity in irradiation-resistant cell line. In contrast, rapamycin undermined miR-101-3p inhibitor-mediated reduction of irradiation sensitivity in irradiation-sensitive cell line. Besides, miR-101-3p overexpression enhanced the efficacy of radiation in an NSCLC xenograft mouse model. In conclusion, miR-101-3p sensitized A549 cells to irradiation via inhibition of mTOR-signaling pathway.

Highlights

Lung cancer is the leading cause of cancer-associated deaths worldwide, and non-small cell lung cancer (NSCLC) accounts for the majority of lung cancer cases [1]
We demonstrated that miR-101-3p sensitized A549 cells to irradiation via inhibition of mechanistic target of rapamycin (mTOR)-signaling pathway by performing quantitative real-time polymerase chain reaction, colony formation, flow cytometry, Western blot, luciferase reporter, and tumor xenograft in vivo assays
The results showed that miR-101-3p combined with irradiation demonstrated a higher percentage of cells in apoptosis than that of the miR-NC group in A549R cells (Figure 2g), while miR-101-3p depletion combined with irradiation significantly decreased the ratio of apoptotic A549 cells (Figure 2h)

Summary

Introduction

Lung cancer is the leading cause of cancer-associated deaths worldwide, and non-small cell lung cancer (NSCLC) accounts for the majority of lung cancer cases [1]. MicroRNAs (miRNAs), small noncoding RNAs, are aberrantly expressed in a variety of cancer cells and play irreplaceable roles in regulating gene expressions, thereby modulating downstream signaling pathways and affecting cancer development and progression [5] It is well-documented that miRNAs may be novel molecular biomarkers of biochemical recurrence for NSCLC patients and determine prognosis and response to therapy [6,7]. Researchers indicated that miR-101-3p blocks the phosphatidylinositol 3-kinase (PI3K)/AKTsignaling pathway by targeting metastasis associated lung adenocarcinoma transcript 1, leading to the inhibition of growth and metastasis of NSCLC [14]. Those data taken together suggest that miR-101-3p may act as a tumor suppressor gene in NSCLC. It has been reported that miR-101-3p increases the

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