Radiosensitizing effects of miR‐18a‐5p on lung cancer stem‐like cells via downregulating both ATM and HIF‐1α

Abstract

Lung cancer is one of the main causes of cancer mortality globally. Most patients received radiotherapy during the course of disease. However, radioresistance generally occurs in the majority of these patients, leading to poor curative effect, and the underlying mechanism remains unclear. In the present study, miR‐18a‐5p expression was downregulated in irradiated lung cancer cells. Overexpression of miR‐18a‐5p increased the radiosensitivity of lung cancer cells and inhibited the growth of A549 xenografts after radiation exposure. Dual luciferase report system and miR‐18a‐5p overexpression identified ataxia telangiectasia mutated (ATM) and hypoxia inducible factor 1 alpha (HIF‐1α) as the targets of miR‐18a‐5p. The mRNA and protein expressions of ATM and HIF‐1α were dramatically downregulated by miR‐18a‐5p in vitro and in vivo. Clinically, plasma miR‐18a‐5p expression was significantly higher in radiosensitive than in radioresistant group (P < .001). The cutoff value of miR‐18a‐5p >2.28 was obtained from receiver operating characteristic (ROC) curve. The objective response rate (ORR) was significantly higher in miR‐18a‐5p‐high group than in miR‐18a‐5p‐low group (P < .001). A tendency demonstrated that the median local progression‐free survival (PFS) from radiotherapy was longer in miR‐18a‐5p‐high than in miR‐18a‐5p‐low group (P = .082). The median overall survival (OS) from radiotherapy was numerically longer in miR‐18a‐5p‐high than in miR‐18a‐5p‐low group (P = .281). The sensitivity and specificity of plasma miR‐18a‐5p to predict radiosensitivity was 87% and 95%, respectively. Collectively, these results indicate that miR‐18a‐5p increases the radiosensitivity in lung cancer cells and CD133+ stem‐like cells via downregulating ATM and HIF‐1α expressions. Plasma miR‐18a‐5p would be an available indicator of radiosensitivity in lung cancer patients.

The dual functional role of MicroRNA‐18a (miR‐18a) in cancer development

“…However, few reports have investigated the mechanism by which plasma miR‐18a contributes to increased radiosensitivity in NSCLC patients. To investigate the role of miR‐18a in NSCLC treatment, a group of researchers enrolled patients with stage IIIa‐IIIb, unresectable lung cancer who were either obtaining a benefit from chemoradiotherapy or exhibited resistance [85]. Consistent with previous studies, the plasma miR‐18a levels were significantly higher in the radiosensitive group than in the radioresistant group.…”

“…These reports provide evidence that plasma miR‐18a may contribute to next‐generation cancer screening via noninvasive liquid biopsy by functioning as a sensitive cancer biomarker. We also summarize findings identifying miR‐18a as a chemoradiotherapy sensitizer, which suggest that miR‐18a could be used to increase radiosensitivity and reverse radioresistance [85]. Finally, we introduce the delivery of anti‐miRNA oligonucleotides by lipid nanoparticles (LNPs) as a new drug design approach [86].…”

The interplay between HIF-1α and noncoding RNAs in cancer

“…In addition to the basic interaction between miRNAs and the 3'-UTR of HIF-1α, miRNA-mediated transcriptional regulation of HIF-1α expression is a common mechanism in cancer progression. MiR-214 upregulates HIF-1α and VEGFA with the suppression of ING4 to promote the invasion, proliferation and migration of non-small-cell lung cancer cells [132], and a possible mechanism is that ING4, which is recruited by egl-9 family hypoxia-inducible factor 1 (EGLN1), unexpectedly miR-338-3p hepatocellular cancer inhibits viability and induces apoptosis, enhances the sensitivity to sorafenib post-transcriptional regulation [102] miR-138 ovarian cancer inhibits migration and invasion post-transcriptional regulation [103] miR-576-3p glioma inhibits migration and proangiogenic abilities post-transcriptional regulation [104] miR-18a-5p lung cancer promotes radiosensitivity post-transcriptional regulation [105] miR-3662 hepatocellular cancer inhibits warburg effect and growth post-transcriptional regulation [106] miR-143-5p gallbladder cancer inhibits EMT, proliferation, migration and invasion post-transcriptional regulation [107] miR-143 cervical cancer inhibits proliferation, promotes apoptosis post-transcriptional regulation [108] miR-106a/b breast cancer inhibits stem-like cell specific, self-renewal and sphere-forming phenotype post-transcriptional regulation [109] miR-199a-5p melanoma inhibits proliferation, induces arrest post-transcriptional regulation [110] miR-20b osteosarcoma inhibits proliferation and invasion post-transcriptional regulation [111] miR-18b melanoma inhibits proliferation, induces arrest, inhibits the glycolysis post-transcriptional regulation [112] miR-622 lung cancer inhibits migration and invasion post-transcriptional regulation [113] miR-33a melanoma inhibits proliferation, invasion and metastasis post-transcriptional regulation [114] miR-338 nasopharyngeal carcinoma inhibits migration and proliferation post-transcriptional regulation [115] miR-20b hepatocellular cancer inhibits proliferation, inhibits apoptosis post-transcriptional regulation [116] miR-199a-5p multiple myeloma inhibits migration, promotes adhesion, inhibits endothelial cells migration post-transcriptional regulation [117] miR-199b prostate cancer inhibits growth, promotes death post-transcriptional regulation [118] miR-199a hepatocellular cancer inhibits proliferation post-transcriptional regulation [119] miR-138 renal cancer promotes apoptosis, inhibits migration post-transcriptional regulation [120] miR-22 colon cancer inhibits endothelial cell growth and invasion post-transcriptional ...…”

Radiosensitization of Hepatocellular Carcinoma through Targeting Radio-Associated MicroRNA

“…miR-203a-3p targeting ATM was found to repress the proliferation, migration, and invasion of ovarian cancer cells and to facilitate their apoptosis through the Akt/GSK-3β/Snail signaling pathway [7]. Moreover, up-regulation of miR-18a-5p inhibited the levels of expression of ATM and pATM (phospho S1981) and enhanced the radiosensitivity of A549 and CD133 + stem-like cells [8]. Enhanced miR-203 also inhibited ATM activity and suppressed the ATM-Snail pathway, increasing E-cadherin, and thereby preventing the migration and invasion of gastric cancer cells [9].…”