Journal
BRITISH JOURNAL OF CANCER
Volume 107, Issue 8, Pages 1361-1373Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/bjc.2012.382
Keywords
miRNA; microarray; lung cancer; small cell lung cancer; non-small cell lung cancer; radiotherapy
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Funding
- Swedish Cancer Society
- Stockholm Cancer Society
- Stockholm County Council
- Swedish Research Foundation
- Swedish Childhood Cancer Foundation
- European Union
- Higher Education Commission in Pakistan
- Ministry of Higher Education and Scientific Research in Iraqi-Kurdistan Regional Government
- Wenner-Gren Foundation
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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. CONCLUSION: miRNA profiling of LC revealed putative RT resistance signalling circuits, which might help in sensitisation of LC to RT. British Journal of Cancer (2012) 107, 1361-1373. doi:10.1038/bjc.2012.382 www.bjcancer.com Published online 28 August 2012 (C) 2012 Cancer Research UK
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