Open Access

ARTICLE

miR-449a Suppresses LDHA-Mediated Glycolysis to Enhance the Sensitivity of Non-Small Cell Lung Cancer Cells to Ionizing Radiation

Liang Li^*1, Huijuan Liu^*1, Lianjiang Du^†, Pan Xi^*, Qian Wang^*, Yanqin Li^‡, Di Liu^§

* Department of Radiotherapy, Shaanxi Provincial Tumor Hospital, Xi’an, P.R. China
† Department of Oncology, Ankang City Central Hospital, Ankang, P.R. China
‡ School of Public Health, Xi’an Jiaotong University Health Science Center, Xi’an, P.R. China
§ Department of Oncology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, P.R. China
1 These authors provided equal contribution to this work.

Oncology Research 2018, 26(4), 547-556. https://doi.org/10.3727/096504017X15016337254605

Abstract

MicroRNA dysregulation contributes to malignant progression, dissemination, and profound treatment resistance in multiple cancers. miR-449a is recognized as a tumor suppresser. However, the roles of miR-449a in lung cancer initiation and progression are largely unknown. Our study aims to investigate the roles and underlying mechanism of miR-449a in modulating sensitivity to ionizing radiation (IR) in non-small cell lung cancer (NSCLC). Lung cancer cells were transfected with miR-449a mimics or negative control and exposed to IR; the levels of target protein, glycolysis, cell viability, apoptosis, and DNA damage were examined. miR-449a was suppressed in lung cancer tissues and cancer cells (A549 and H1299). IR exposure significantly increased the expression of miR-449a in A549 cells at doses ranging from 4 to 8 Gy at 24 h, whereas no significant change in miR-449a was found in H1299 cells after IR. When A549 cells were exposed to IR at a dose of 8 Gy, the miR-449a level only had an acute increase within 12 h. miR-449a restoration dramatically suppressed IR-induced cell apoptosis and DNA damage in both A549 and H1299 cells. Bioinformatics analysis indicated that lactate dehydrogenase A (LDHA) was a potential target of miR-449a. miR-449a mimic transfection substantially suppressed the LDHA expression and production of lactate catalyzed by LDHA as well as glucose uptake. We confirmed that miR-449a could bind to the 3'-UTR of LDHA mRNA using luciferase reporter assay. LDHA siRNA-transfected cells showed enhanced cell apoptosis and DNA damage in response to IR exposure. miR-449a upregulation enhanced IR sensitivity of lung cancer cells by suppressing LDHA and the subsequent glycolysis.

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