Abstract
Radiotherapy remains one of the major treatments for non-small cell lung cancer (NSCLC) patients; whereas intrinsic or acquired radioresistance limits its efficacy. Nevertheless, most studies so far have only focused on acquired resistance. The exact mechanisms of intrinsic radioresistance in NSCLC are still unclear. A few studies have suggested that epithelial–mesenchymal transition (EMT) is associated with radioresistance in NSCLC. However, little is known about whether the abnormal expression of specific microRNAs induces both EMT and radioresistance. We previously found that miR-410 has multiple roles as an oncomiRNA in NSCLC. In this study, we revealed that miR-410 overexpression promoted EMT and radioresistance, accompanied by enhanced DNA damage repair both in vitro and in vivo. Conversely, knockdown of miR-410 showed the opposite effects. We further demonstrated that PTEN was a direct target of miR-410 by using bioinformatic tools and dual-luciferase reporter assays, and the miR-410-induced EMT and radioresistance were reversed by PI3K, Akt, and mTOR inhibitors or by restoring the expression of PTEN in NSCLC cells. In addition, we preliminarily found that the expression of miR-410 was positively correlated with EMT and negatively associated with the expression of PTEN in NSCLC specimens. In summary, these results demonstrated that miR-410 is an important regulator on enhancing both NSCLC EMT and radioresistance by targeting the PTEN/PI3K/mTOR axis. The findings suggest that miR-410-induced EMT might significantly contribute to the enhanced radioresistance. Therefore, miR-410 may serve as a potential biomarker or therapeutic target for NSCLC radiotherapy.
Highlights
Radiotherapy (RT), stereotactic body radiation therapy (SBRT) in particular, is a standard treatment for early-stage non-small cell lung cancer (NSCLC) patients who are unfit for surgery.[1,2] In addition, many patients diagnosed with NSCLC are already at an advanced stage,[3] and RT/chemotherapy is recommended as radical or palliative treatment.[4]
We revealed that miR-410 induced both Among them, the PI3K/Akt and mTOR signaling pathways have NSCLC epithelial–mesenchymal transition (EMT) and radioresistance by targeting the PTEN/PI3K/mTOR been demonstrated to be closely associated with PTEN,[36] which axis in vitro and in vivo, and the promotion of radioresistance might be associated with enhanced DNA damage repair
The PI3K/mTOR pathway contributed to miR-410-induced EMT
Summary
Radiotherapy (RT), stereotactic body radiation therapy (SBRT) in particular, is a standard treatment for early-stage non-small cell lung cancer (NSCLC) patients who are unfit for surgery.[1,2] In addition, many patients diagnosed with NSCLC are already at an advanced stage,[3] and RT/chemotherapy is recommended as radical or palliative treatment.[4]. MiR-410 was found to increase the levels of phosphory- miR-410 directly targeted PTEN in NSCLC cells lated Akt in NSCLC.[26] Interestingly, A549 and H1299 cells with To identify the mechanism underlying the miR-410-induced EMT wild-type EGFR exhibited resistance to radiation and were used as radioresistant cells.[11,27,28] Stabilization or upregulation of Slug by the inhibition of Gsk3β or activation of the β-catenin pathway process and radioresistance, TargetScan, DIANA-microT-CDS, and miRanda were used to predict the targets of miR-410 (Fig. 3a). The mRNA levels of PTEN showed no difference with indicate that miR-410 may be a potential biomarker or therapeutic the change in miR-410 expression (Supplemental Fig. S3) These results confirmed that PTEN was a direct target of miR-410 and that it was posttranscriptionally regulated by miR-
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