title: Radiation-induced miR-208a increases the proliferation and radioresistance by targeting p21 in human lung cancer cells.
abstract: BACKGROUND
  Lung cancer has long been the most dangerous malignant tumor among males in both well developed and poorly developed countries. Radiotherapy plays a critical role in the curative management of inoperable non-small cell lung cancer (NSCLC) and is also used as a post-surgical treatment in lung cancer patients. Radioresistance is an important factor that limits the efficacy of radiotherapy for NSCLC patients. Increasing evidence suggests that microRNAs (miRNAs) possess diverse cellular regulatory roles in radiation responses.
  
  
  METHODS
  In this study, we used miRNA microarray technology to identify serum miRNAs that were differentially expressed before and after radiotherapy in lung cancer patients. We further examined the biological function of miR-208a on cell viability, apoptotic death and cell cycle distribution in human lung cancer cells and explored the probable mechanism.
  
  
  RESULTS
  Nine miRNAs, including miR-29b-3p, miR-200a-3p, and miR-126-3p were significantly down-regulated, whereas miR-208a was the only miRNA that was up-regulated in the serum of the patients after radiation treatment (P < 0.05). The expression of miR-208a could be induced by X-ray irradiation in lung cancer cells. Forced expression of miR-208a promoted cell proliferation and induced radioresistance via targeting p21 with a corresponding activation of the AKT/mTOR pathway in lung cancer cells, whereas down-regulation of miR-208a resulted in the opposite effects. In addition, down-regulation of miR-208a increased the percentage of cells undergoing apoptosis and inhibited the G1 phase arrest in NSCLC cells. Moreover, miR-208a from the serum exosome fraction of lung cancer patients could shuttle to A549 cells in a time-dependent manner, which was likely to contribute to the subsequent biological effects.
  
  
  CONCLUSIONS
  The present study provides evidence that miR-208a can affect the proliferation and radiosensitivity of human lung cancer cells by targeting p21 and can be transported by exosomes. Thus, miR-208a may serve as a potential therapeutic target for lung cancer patients.
authors.affiliation: Department of Radiation Oncology, Changzhou Cancer Hospital, Soochow University, Changzhou, 213001, China. tangyiting001@163.com.
authors.forename: Yiting
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Department of Radiation Oncology, Anhui Provincial Hospital, Hefei, 213001, China. 383305848@qq.com.
authors.forename: Yayun
authors.initials: Y
authors.lastname: Cui
authors.affiliation: State Key Laboratory Breeding Base of Marine Genetic Resources, Third Institute of Oceanography, State Oceanic Administration, Xiamen, 361005, China. 287773637@qq.com.
authors.forename: Zengpeng
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department School of Information Science and Engineering, Changzhou University, Changzhou, 213164, China. jzqtec@163.com.
authors.forename: Zhuqing
authors.initials: Z
authors.lastname: Jiao
authors.affiliation: Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong University, Jinan, 250117, China. 923325629@qq.com.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: School of Radiation Medicine and Protection and Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, 215123, China. 578576464@qq.com.
authors.forename: Yan
authors.initials: Y
authors.lastname: He
authors.affiliation: Department of Gastroenterology, First People's Hospital of Xuzhou, Xuzhou, 221002, China. 2586303814@qq.com.
authors.forename: Guangxia
authors.initials: G
authors.lastname: Chen
authors.affiliation: Department of Gastroenterology, First People's Hospital of Xuzhou, Xuzhou, 221002, China. 2586303814@qq.com.
authors.forename: Guangxia
authors.initials: G
authors.lastname: Cheng
authors.affiliation: Department of Gastroenterology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, 214002, China. zhouqunyan82@126.com.
authors.forename: Qunyan
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: School of Radiation Medicine and Protection and Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, 215123, China. 425927180@qq.com.
authors.forename: Wenjie
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Radiation Oncology, Changzhou Cancer Hospital, Soochow University, Changzhou, 213001, China. 83559808@qq.com.
authors.forename: Xifa
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Radiation Oncology, Changzhou Cancer Hospital, Soochow University, Changzhou, 213001, China. judongluo@163.com.
authors.forename: Judong
authors.initials: J
authors.lastname: Luo
authors.affiliation: School of Radiation Medicine and Protection and Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, 215123, China. zhang.shuyu@hotmail.com.
authors.forename: Shuyu
authors.initials: S
authors.lastname: Zhang
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects; D006801:Humans; D008175:Lung Neoplasms / Q000097:blood / Q000235:genetics / Q000532:radiotherapy*; D035683:MicroRNAs / Q000097:blood / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D011836:Radiation Tolerance; D015398:Signal Transduction / Q000528:radiation effects; D015854:Up-Regulation
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C550906:MIRN208 microRNA, human; D035683:MicroRNAs