miR-15a/16 Enhances Radiation Sensitivity of Non-Small Cell Lung Cancer Cells by Targeting the TLR1/NF-κB Signaling Pathway

• Published in: International journal of radiation oncology, biology, physics Vol. 91; no. 1; pp. 73 - 81
• Main Authors: Lan, Fengming, MS, Yue, Xiao, MS, Ren, Gang, MD, Li, Hongqi, MD, Ping, Li, MS, Wang, Yingjie, MS, Xia, Tingyi, MD
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2015
• Subjects: 3' Untranslated Regions; Adenocarcinoma - metabolism; Adenocarcinoma - radiotherapy; ANIMAL TISSUES; Animals; APOPTOSIS; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - radiotherapy; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - radiotherapy; Cell Line, Tumor; Cell Survival - radiation effects; CORRELATIONS; Down-Regulation; Hematology, Oncology and Palliative Medicine; Humans; LUCIFERASE; Luciferases - metabolism; Lung - metabolism; Lung Neoplasms - metabolism; Lung Neoplasms - radiotherapy; LUNGS; MICE; Mice, Nude; MicroRNAs - metabolism; NEOPLASMS; NF-kappa B - metabolism; POTENTIALS; Radiation Tolerance - physiology; Radiology; RADIOLOGY AND NUCLEAR MEDICINE; RADIOSENSITIVITY; Random Allocation; RECEPTORS; Toll-Like Receptor 1 - genetics; Toll-Like Receptor 1 - metabolism; Tumor Stem Cell Assay
• ISSN: 0360-3016; 1879-355X
• DOI: 10.1016/j.ijrobp.2014.09.021

Purpose Many miRNAs have been identified as essential issues and core determining factors in tumor radiation. Recent reports have demonstrated that miRNAs and Toll-like receptors could exert reciprocal effects to control cancer development in various ways. However, a novel role of miR-15a/16 in enhancing radiation sensitivity by directly targeting TLR1 has not been reported, to our knowledge. Methods and Materials Bioinformatic analyses, luciferase reporter assay, biochemical assays, and subcutaneous tumor establishment were used to characterize the signaling pathways of miRNA-15a/16 in response to radiation treatment. Results First, an inverse correlation between the expression of miR-15a/16 and TLR1 protein was revealed in non-small cell lung cancer (NSCLC) and normal lung tissues. Next, we corroborated that miR-15a/16 specifically bound to TLR1 3′UTR and inhibited the expression of TLR1 in H358 and A549 cells. Furthermore, miR-15a/16 downregulated the activity of the NF-κB signaling pathway through TLR1. In addition, overexpression of miR-15a/16 inhibited survival capability and increased radiation-induced apoptosis, resulting in enhancement of radiosensitivity in H358 and A549 cells. Finally, subcutaneous tumor bearing NSCLC cells in a nude mice model was established, and the results showed that combined groups (miR-15a/16 + radiation) inhibited tumor growth more significantly than did radiation alone. Conclusions We mainly elucidate that miRNA-15a/16 can enhance radiation sensitivity by regulating the TLR1/NF-κB signaling pathway and act as a potential therapeutic approach to overcome radioresistance for lung cancer treatment.