miR-410 induces both epithelial–mesenchymal transition and radioresistance through activation of the PI3K/mTOR pathway in non-small cell lung cancer

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.

miR‑454‑3p inhibits non‑small cell lung cancer cell proliferation and metastasis by targeting TGFB2

“…Increasing studies have revealed that miRNAs are closely associated with tumor cell proliferation, migration, invasion, drug resistance and apoptosis ( 6 , 7 ). For instance, miR-410 was revealed to promote epithelial-mesenchymal transition (EMT) and radio-resistance by targeting the PI3K/mTOR axis in NSCLC ( 8 ). miR-219 functioned as a tumor suppressor, which inhibited NSCLC and ovarian cancer cell growth and metastasis ( 9 , 10 ).…”

miR-4461 Regulates the Proliferation and Metastasis of Ovarian Cancer Cells and Cisplatin Resistance

“…PTEN is an important tumor suppressor, and has been found to participate in the tumorigenesis and progression via downregulation of PI3-K/Akt pathway (18)(19)(20). PTEN was a vital regulator of cell reproduction, cell cycle, apoptosis and metastasis, and its low expression might cause tumor progression including OC (21)(22)(23).…”

MiRNAs and Cancer: Key Link in Diagnosis and Therapy

“…The EMT process not only leads to the invasion and migration of tumor cells, but also results in therapy resistance in cancer patients [58]. The overexpression of miR-410 enhances EMT and radiotherapy resistance by increasing DNA damage repair and regulates EMT through PTEN/PI3K/mTOR axis which leads to the radiotherapy resistance in non-small cell lung cancer (NSCLC) [59].…”