title: miRNA-214 modulates radiotherapy response of non-small cell lung cancer cells through regulation of p38MAPK, apoptosis and senescence.
abstract: BACKGROUND
  Radio- and chemotherapy (RT/CT) resistance hampers success in combating small and non-small cell lung cancers (SCLC/NSCLC). The underlying molecular mechanisms of RT/CT resistance of LCs are multifactorial and have been understood in part hitherto. miRNAs, key regulators of mRNAs, are well-recognised oncomirs; however, their role in regulating RT response remains poorly understood.
  
  
  METHODS
  Six human NSCLC and five SCLC cell lines with different SF2 values were investigated. Using microarray we examined whether expression of miRNAs is linked to the RT resistance of NSCLCs or SCLCs. Obtained data were validated by quantitative real-time PCR. Apoptosis and senescence were analysed using siRNA transfection, western blot and flow cytometry.
  
  
  RESULTS
  miRNA-21, miRNA-1827, miRNA-214, miRNA-339-5p, miRNA-625, miRNA-768-3p, miRNA-523-3p, miRNA-1227, miRNA-324-5p, miRNA-423-3p, miRNA-1301 and miRNA-1249 are differentially expressed in LC cells. miRNA-214 is upregulated in RT-resistant NSCLC cells relative to radiosensitive counterparts. Considering miRNA-214 as a putative regulator of RT resistance, we demonstrate that knockdown of miRNA-214 in radioresistant NSCLCs sensitised them to RT by stimulation of senescence. Consistently, overexpression of miRNA-214 in radiosensitive NSCLCs protected against RT-induced apoptosis. Protection was mediated by p38MAPK, as downregulation of this kinase could reverse the miRNA-214 overexpression-induced resistance of NSCLC cells.
  
  
  CONCLUSIONS
  miRNA profiling of LC revealed putative RT resistance signalling circuits, which might help in sensitisation of LC to RT.
authors.affiliation: Department of Oncology-Pathology, Karolinska Biomics Center, Karolinska Institutet, Stockholm, Sweden.
authors.forename: H
authors.initials: H
authors.lastname: Salim
authors.forename: N S
authors.initials: NS
authors.lastname: Akbar
authors.forename: D
authors.initials: D
authors.lastname: Zong
authors.forename: A H
authors.initials: AH
authors.lastname: Vaculova
authors.forename: R
authors.initials: R
authors.lastname: Lewensohn
authors.forename: A
authors.initials: A
authors.lastname: Moshfegh
authors.forename: K
authors.initials: K
authors.lastname: Viktorsson
authors.forename: B
authors.initials: B
authors.lastname: Zhivotovsky
mesh_terms: D017209:Apoptosis / Q000235:genetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000532:radiotherapy; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000235:genetics*; D020869:Gene Expression Profiling; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000532:radiotherapy; D035683:MicroRNAs / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D015398:Signal Transduction; D055752:Small Cell Lung Carcinoma / Q000235:genetics* / Q000532:radiotherapy; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics
chemical_list: C547397:MIRN214 microRNA, human; D035683:MicroRNAs; D048051:p38 Mitogen-Activated Protein Kinases