Table of Contents Author Guidelines Submit a Manuscript
BioMed Research International
Volume 2014 (2014), Article ID 296747, 16 pages
http://dx.doi.org/10.1155/2014/296747
Research Article

Integration Analysis of MicroRNA and mRNA Expression Profiles in Human Peripheral Blood Lymphocytes Cultured in Modeled Microgravity

1Dipartimento di Biologia, Università degli Studi di Padova, Via U. Bassi 58/B, 35131 Padova, Italy
2Laboratori Nazionali di Legnaro, INFN, Viale dell’Università 2, Legnaro, 35020 Padova, Italy

Received 16 April 2014; Revised 22 May 2014; Accepted 22 May 2014; Published 23 June 2014

Academic Editor: Mariano Bizzarri

Copyright © 2014 C. Girardi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. R. H. Fitts, D. R. Riley, and J. J. Widrick, “Functional and structural adaptations of skeletal muscle to microgravity,” Journal of Experimental Biology, vol. 204, no. 18, pp. 3201–3208, 2001. View at Google Scholar · View at Scopus
  2. M. Narici, B. Kayser, P. Barattini, and P. Cerretelli, “Effects of 17-day spaceflight on electrically evoked torque and cross-sectional area of the human triceps surae,” European Journal of Applied Physiology, vol. 90, no. 3-4, pp. 275–282, 2003. View at Publisher · View at Google Scholar · View at Scopus
  3. S. Trappe, D. Costill, P. Gallagher et al., “Exercise in space: human skeletal muscle after 6 months aboard the International Space Station,” Journal of Applied Physiology, vol. 106, no. 4, pp. 1159–1168, 2009. View at Publisher · View at Google Scholar · View at Scopus
  4. S. I. M. Carlsson, M. T. S. Bertilaccio, E. Ballabio, and J. A. M. Maier, “Endothelial stress by gravitational unloading: effects on cell growth and cytoskeletal organization,” Biochimica et Biophysica Acta, vol. 1642, no. 3, pp. 173–179, 2003. View at Publisher · View at Google Scholar · View at Scopus
  5. M. Infanger, P. Kossmehl, M. Shakibaei et al., “Induction of three-dimensional assembly and increase in apoptosis of human endothelial cells by simulated microgravity: impact of vascular endothelial growth factor,” Apoptosis, vol. 11, no. 5, pp. 749–764, 2006. View at Publisher · View at Google Scholar · View at Scopus
  6. R. M. Baevsky, V. M. Baranov, I. I. Funtova et al., “Autonomic cardiovascular and respiratory control during prolonged spaceflights aboard the International Space Station,” Journal of Applied Physiology, vol. 103, no. 1, pp. 156–161, 2007. View at Publisher · View at Google Scholar · View at Scopus
  7. J. D. Sibonga, H. J. Evans, H. G. Sung et al., “Recovery of spaceflight-induced bone loss: bone mineral density after long-duration missions as fitted with an exponential function,” Bone, vol. 41, no. 6, pp. 973–978, 2007. View at Publisher · View at Google Scholar · View at Scopus
  8. J. H. Keyak, A. K. Koyama, A. LeBlanc, Y. Lu, and T. F. Lang, “Reduction in proximal femoral strength due to long-duration spaceflight,” Bone, vol. 44, no. 3, pp. 449–453, 2009. View at Publisher · View at Google Scholar · View at Scopus
  9. O. Ullrich, K. Huber, and K. Lang, “Signal transduction in cells of the immune system in microgravity,” Cell Communication and Signaling, vol. 6, article 9, 2008. View at Publisher · View at Google Scholar · View at Scopus
  10. B. E. Crucian, R. P. Stowe, D. L. Pierson, and C. F. Sams, “Immune system dysregulation following short- vs long-duration spaceflight,” Aviation Space and Environmental Medicine, vol. 79, no. 9, pp. 835–843, 2008. View at Publisher · View at Google Scholar · View at Scopus
  11. G. Sonnenfeld, J. S. Butel, and W. T. Shearer, “Effects of the space flight environment on the immune system,” Reviews on Environmental Health, vol. 18, no. 1, pp. 1–17, 2003. View at Google Scholar · View at Scopus
  12. G. Sonnenfeld, “Editorial: space flight modifies T cell activation—role of microgravity,” Journal of Leukocyte Biology, vol. 92, no. 6, pp. 1125–1126, 2012. View at Google Scholar
  13. A. Semov, N. Semova, C. Lacelle et al., “Alterations in TNF- and IL-related gene expression in space-flown WI38 human fibroblasts,” The FASEB Journal, vol. 16, no. 8, pp. 899–901, 2002. View at Google Scholar · View at Scopus
  14. T. T. Chang, I. Walther, C.-F. Li et al., “The Rel/NF-κB pathway and transcription of immediate early genes in T cell activation are inhibited by microgravity,” Journal of Leukocyte Biology, vol. 92, no. 6, pp. 1133–1145, 2012. View at Publisher · View at Google Scholar · View at Scopus
  15. M. L. Lewis, L. A. Cubano, B. Zhao et al., “cDNA microarray reveals altered cytoskeletal gene expression in space-flown leukemic T lymphocytes (Jurkat),” The FASEB Journal, vol. 15, no. 10, pp. 1783–1785, 2001. View at Google Scholar · View at Scopus
  16. S. J. Pardo, M. J. Patel, M. C. Sykes et al., “Simulated microgravity using the Random Positioning Machine inhibits differentiation and alters gene expression profiles of 2T3 preosteoblasts,” American Journal of Physiology, vol. 288, no. 6, pp. C1211–C1221, 2005. View at Publisher · View at Google Scholar · View at Scopus
  17. M. Monticone, Y. Liu, N. Pujic, and R. Cancedda, “Activation of nervous system development genes in bone marrow derived mesenchymal stem cells following spaceflight exposure,” Journal of Cellular Biochemistry, vol. 111, no. 2, pp. 442–452, 2010. View at Publisher · View at Google Scholar · View at Scopus
  18. D. Grimm, J. Bauer, P. Kossmehl et al., “Simulated microgravity alters differentiation and increases apoptosis in human follicular thyroid carcinoma cells,” The FASEB Journal, vol. 16, no. 6, pp. 604–606, 2002. View at Google Scholar · View at Scopus
  19. M. Maccarrone, N. Battista, M. Meloni et al., “Creating conditions similar to those that occur during exposure of cells to microgravity induces apoptosis in human lymphocytes by 5-lipoxygenase-mediated mitochondrial uncoupling and cytochrome c release,” Journal of Leukocyte Biology, vol. 73, no. 4, pp. 472–481, 2003. View at Publisher · View at Google Scholar · View at Scopus
  20. S. J. Crawford-Young, “Effects of microgravity on cell cytoskeleton and embryogenesis,” International Journal of Developmental Biology, vol. 50, no. 2-3, pp. 183–191, 2006. View at Publisher · View at Google Scholar · View at Scopus
  21. N. E. Ward, N. R. Pellis, S. A. Risin, and D. Risin, “Gene expression alterations in activated human T-cells induced by modeled microgravity,” Journal of Cellular Biochemistry, vol. 99, no. 4, pp. 1187–1202, 2006. View at Publisher · View at Google Scholar · View at Scopus
  22. J. Q. Clement, S. M. Lacy, and B. L. Wilson, “Gene expression profiling of human epidermal keratinocytes in simulated microgravity and recovery cultures,” Genomics, Proteomics and Bioinformatics, vol. 6, no. 1, pp. 8–28, 2008. View at Publisher · View at Google Scholar · View at Scopus
  23. R. Kumari, K. P. Singh, and J. W. DuMond Jr., “Simulated microgravity decreases DNA repair capacity and induces DNA damage in human lymphocytes,” Journal of Cellular Biochemistry, vol. 107, no. 4, pp. 723–731, 2009. View at Publisher · View at Google Scholar · View at Scopus
  24. C.-Y. Kang, L. Zou, M. Yuan et al., “Impact of simulated microgravity on microvascular endothelial cell apoptosis,” European Journal of Applied Physiology, vol. 111, no. 9, pp. 2131–2138, 2011. View at Publisher · View at Google Scholar · View at Scopus
  25. J. Krützfeldt, M. N. Poy, and M. Stoffel, “Strategies to determine the biological function of microRNAs,” Nature Genetics, vol. 38, no. 1, pp. S14–S19, 2006. View at Publisher · View at Google Scholar · View at Scopus
  26. C. A. Nickerson, C. M. Ott, J. W. Wilson et al., “Low-shear modeled microgravity: a global environmental regulatory signal affecting bacterial gene expression, physiology, and pathogenesis,” Journal of Microbiological Methods, vol. 54, no. 1, pp. 1–11, 2003. View at Publisher · View at Google Scholar · View at Scopus
  27. K. Arunasri, M. Adil, K. Venu Charan, C. Suvro, S. Himabindu Reddy, and S. Shivaji, “Effect of simulated microgravity on E. coli K12 MG1655 growth and gene expression,” PLoS ONE, vol. 8, no. 3, Article ID e57860, 2013. View at Publisher · View at Google Scholar · View at Scopus
  28. O. Marcu, M. P. Lera, M. E. Sanchez et al., “Innate immune responses of Drosophila melanogaster are altered by spaceflight,” PLoS ONE, vol. 6, no. 1, Article ID e15361, 2011. View at Publisher · View at Google Scholar · View at Scopus
  29. Y. Honda, A. Higashibata, Y. Matsunaga et al., “Genes down-regulated in spaceflight are involved in the control of longevity in Caenorhabditis elegans,” Scientific Reports, vol. 2, article 487, 2012. View at Publisher · View at Google Scholar · View at Scopus
  30. A. I. Manzano, J. J. W. A. van Loon, P. C. M. Christianen, J. M. Gonzalez-Rubio, F. J. Medina, and R. Herranz, “Gravitational and magnetic field variations synergize to cause subtle variations in the global transcriptional state of Arabidopsis in vitro callus cultures,” BMC Genomics, vol. 13, no. 1, article 105, 2012. View at Publisher · View at Google Scholar · View at Scopus
  31. D. P. Bartel, “MicroRNAs: target recognition and regulatory functions,” Cell, vol. 136, no. 2, pp. 215–233, 2009. View at Publisher · View at Google Scholar · View at Scopus
  32. H. Guo, N. T. Ingolia, J. S. Weissman, and D. P. Bartel, “Mammalian microRNAs predominantly act to decrease target mRNA levels,” Nature, vol. 466, no. 7308, pp. 835–840, 2010. View at Publisher · View at Google Scholar · View at Scopus
  33. V. Huang, Y. Qin, J. Wang et al., “RNAa is conserved in mammalian cells,” PLoS ONE, vol. 5, no. 1, Article ID e8848, 2010. View at Publisher · View at Google Scholar · View at Scopus
  34. L. B. Frankel, N. R. Christoffersen, A. Jacobsen, M. Lindow, A. Krogh, and A. H. Lund, “Programmed cell death 4 (PDCD4) is an important functional target of the microRNA miR-21 in breast cancer cells,” The Journal of Biological Chemistry, vol. 283, no. 2, pp. 1026–1033, 2008. View at Publisher · View at Google Scholar · View at Scopus
  35. M. N. Poy, M. Spranger, and M. Stoffel, “microRNAs and the regulation of glucose and lipid metabolism,” Diabetes, Obesity and Metabolism, vol. 9, no. 2, pp. 67–73, 2007. View at Publisher · View at Google Scholar · View at Scopus
  36. N. Stern-Ginossar, N. Elefant, A. Zimmermann et al., “Host immune system gene targeting by a viral miRNA,” Science, vol. 317, no. 5836, pp. 376–381, 2007. View at Publisher · View at Google Scholar · View at Scopus
  37. C. J. Marsit, K. Eddy, and K. T. Kelsey, “MicroRNA responses to cellular stress,” Cancer Research, vol. 66, no. 22, pp. 10843–10848, 2006. View at Publisher · View at Google Scholar · View at Scopus
  38. P. M. Voorhoeve, C. le Sage, M. Schrier et al., “A genetic screen implicates miRNA-372 and miRNA-373 as oncogenes in testicular germ cell tumors,” Cell, vol. 124, no. 6, pp. 1169–1181, 2006. View at Publisher · View at Google Scholar · View at Scopus
  39. E. A. C. Wiemer, “The role of microRNAs in cancer: no small matter,” European Journal of Cancer, vol. 43, no. 10, pp. 1529–1544, 2007. View at Publisher · View at Google Scholar · View at Scopus
  40. W. C. S. Cho, “OncomiRs: the discovery and progress of microRNAs in cancers,” Molecular Cancer, vol. 6, article 60, 2007. View at Publisher · View at Google Scholar · View at Scopus
  41. S. Mi, J. Lu, M. Sun et al., “MicroRNA expression signatures accurately discriminate acute lymphoblastic leukemia from acute myeloid leukemia,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 50, pp. 19971–19976, 2007. View at Publisher · View at Google Scholar · View at Scopus
  42. S. M. Hammond, “MicroRNAs as tumor suppressors,” Nature Genetics, vol. 39, no. 5, pp. 582–583, 2007. View at Publisher · View at Google Scholar · View at Scopus
  43. A. Bisognin, G. Sales, A. Coppe, S. Bortoluzzi, and C. Romualdi, “MAGIA2: from miRNA and genes expression data integrative analysis to microRNA-transcription factor mixed regulatory circuits (2012 update),” Nucleic Acids Research, vol. 40, no. 1, pp. W13–W21, 2012. View at Publisher · View at Google Scholar · View at Scopus
  44. M. Mognato and L. Celotti, “Modeled microgravity affects cell survival and HPRT mutant frequency, but not the expression of DNA repair genes in human lymphocytes irradiated with ionising radiation,” Mutation Research, vol. 578, no. 1-2, pp. 417–429, 2005. View at Publisher · View at Google Scholar · View at Scopus
  45. B. R. Unsworth and P. I. Lelkes, “Growing tissues in microgravity,” Nature Medicine, vol. 4, no. 8, pp. 901–907, 1998. View at Publisher · View at Google Scholar · View at Scopus
  46. S.-M. Hou, F. J. Van Dam, F. De Zwart et al., “Validation of the human T-lymphocyte cloning assay—ring test report from the EU concerted action on HPRT mutation (EUCAHM),” Mutation Research, vol. 431, no. 2, pp. 211–221, 1999. View at Publisher · View at Google Scholar · View at Scopus
  47. C. Girardi, C. de Pittà, S. Casara et al., “Analysis of miRNA and mRNA expression profiles highlights alterations in ionizing radiation response of human lymphocytes under modeled microgravity,” PLoS ONE, vol. 7, no. 2, Article ID e31293, 2012. View at Publisher · View at Google Scholar · View at Scopus
  48. H. Wang, R. A. Ach, and B. O. Curry, “Direct and sensitive miRNA profiling from low-input total RNA,” RNA, vol. 13, no. 1, pp. 151–159, 2007. View at Publisher · View at Google Scholar · View at Scopus
  49. B. M. Bolstad, R. A. Irizarry, M. Åstrand, and T. P. Speed, “A comparison of normalization methods for high density oligonucleotide array data based on variance and bias,” Bioinformatics, vol. 19, no. 2, pp. 185–193, 2003. View at Publisher · View at Google Scholar · View at Scopus
  50. V. G. Tusher, R. Tibshirani, and G. Chu, “Diagnosis of multiple cancer types by shrunken centroids of gene expression,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, pp. 5116–5121, 2001. View at Google Scholar
  51. G. Sales, E. Calura, P. Martini, and C. Romualdi, “Graphite web: web tool for gene set analysis exploiting pathway topology,” Nucleic Acids Research, vol. 41, pp. 89–97, 2013. View at Google Scholar
  52. F. Xin, M. Li, C. Balch et al., “Computational analysis of microRNA profiles and their target genes suggests significant involvement in breast cancer antiestrogen resistance,” Bioinformatics, vol. 25, no. 4, pp. 430–434, 2009. View at Publisher · View at Google Scholar · View at Scopus
  53. H. Wang and W.-H. Li, “Increasing MicroRNA target prediction confidence by the relative R2 method,” Journal of Theoretical Biology, vol. 259, no. 4, pp. 793–798, 2009. View at Publisher · View at Google Scholar · View at Scopus
  54. D. W. Huang, B. T. Sherman, and R. A. Lempicki, “Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources,” Nature Protocols, vol. 4, no. 1, pp. 44–57, 2009. View at Publisher · View at Google Scholar · View at Scopus
  55. K. J. Livak and T. D. Schmittgen, “Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT method,” Methods, vol. 25, no. 4, pp. 402–408, 2001. View at Publisher · View at Google Scholar · View at Scopus
  56. R. J. Albertini, K. L. Castle, and W. R. Borcherding, “T-cell cloning to detect the mutant 6-thioguanine-resistant lymphocytes present in human peripheral blood,” Proceedings of the National Academy of Sciences of the United States of America, vol. 79, no. 21 I, pp. 6617–6621, 1982. View at Google Scholar · View at Scopus
  57. M. Mognato, C. Girardi, S. Fabris, and L. Celotti, “DNA repair in modeled microgravity: double strand break rejoining activity in human lymphocytes irradiated with γ-rays,” Mutation Research, vol. 663, no. 1-2, pp. 32–39, 2009. View at Publisher · View at Google Scholar · View at Scopus
  58. S. Canova, F. Fiorasi, M. Mognato et al., ““Modeled microgravity” affects cell response to ionizing radiation and increases genomic damage,” Radiation Research, vol. 163, no. 2, pp. 191–199, 2005. View at Publisher · View at Google Scholar · View at Scopus
  59. B. P. Lewis, C. B. Burge, and D. P. Bartel, “Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets,” Cell, vol. 120, no. 1, pp. 15–20, 2005. View at Publisher · View at Google Scholar · View at Scopus
  60. M. S. Cline, M. Smoot, E. Cerami et al., “Integration of biological networks and gene expression data using Cytoscape,” Nature Protocols, vol. 2, no. 10, pp. 2366–2382, 2007. View at Publisher · View at Google Scholar · View at Scopus
  61. F. Censi, A. Giuliani, P. Bartolini, and G. Calcagnini, “A multiscale graph theoretical approach to gene regulation networks: a case study in atrial fibrillation,” IEEE Transactions on Biomedical Engineering, vol. 58, no. 10, pp. 2943–2946, 2011. View at Publisher · View at Google Scholar · View at Scopus
  62. P. Chen, C. Price, Z. Li et al., “miR-9 is an essential oncogenic microRNA specifically overexpressed in mixed lineage leukemia-rearranged leukemia,” Proceedings of the National Academy of Sciences of the United States of America, vol. 110, no. 28, pp. 11511–11516, 2013. View at Publisher · View at Google Scholar · View at Scopus
  63. G. Pignot, G. Cizeron-Clairac, S. Vacher et al., “MicroRNA expression profile in a large series of bladder tumors: identification of a 3-miRNA signature associated with aggressiveness of muscle-invasive bladder cancer,” International Journal of Cancer, vol. 132, no. 11, pp. 2479–2491, 2013. View at Publisher · View at Google Scholar · View at Scopus
  64. H. M. Namløs, L. A. Meza-Zepeda, T. Barøy et al., “Modulation of the osteosarcoma expression phenotype by microRNAs,” PLoS ONE, vol. 7, no. 10, Article ID e48086, 2012. View at Publisher · View at Google Scholar · View at Scopus
  65. P. S. Eis, W. Tam, L. Sun et al., “Accumulation of miR-155 and BIC RNA in human B cell lymphomas,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 10, pp. 3627–3632, 2005. View at Publisher · View at Google Scholar · View at Scopus
  66. Y. Pan, M. Meng, G. Zhang, H. Han, and Q. Zhou, “Oncogenic microRNAs in the genesis of leukemia and lymphoma,” Current Pharmaceutical Design, 2014. View at Publisher · View at Google Scholar
  67. M. V. Iorio, M. Ferracin, C.-G. Liu et al., “MicroRNA gene expression deregulation in human breast cancer,” Cancer Research, vol. 65, no. 16, pp. 7065–7070, 2005. View at Publisher · View at Google Scholar · View at Scopus
  68. Z. Lu, Y. Ye, D. Jiao, J. Qiao, S. Cui, and Z. Liu, “MiR-155 and miR-31 are differentially expressed in breast cancer patients and are correlated with the estrogen receptor and progesterone receptor status,” Oncology Letters, vol. 4, no. 5, pp. 1027–1032, 2012. View at Publisher · View at Google Scholar · View at Scopus
  69. F. Gao, J. Chang, H. Wang, and G. Zhang, “Potential diagnostic value of miR-155 in serum from lung adenocarcinoma patients,” Oncology Reports, vol. 31, no. 1, pp. 351–357, 2014. View at Google Scholar
  70. G. Higgs and F. Slack, “The multiple roles of microRNA-155 in oncogenesis,” Journal of Clinical Bioinformatics, vol. 3, no. 1, p. 17, 2013. View at Google Scholar
  71. H. Fayyad-Kazan, N. Bitar, M. Najar et al., “Circulating miR-150 and miR-342 in plasma are novel potential biomarkers for acute myeloid leukemia,” Journal of Translational Medicine, vol. 11, no. 1, article 31, 2013. View at Publisher · View at Google Scholar · View at Scopus
  72. M. Yanlei, P. Zhang, F. Wang et al., “miR-150 as a potential biomarker associated with prognosis and therapeutic outcome in colorectal cancer,” Gut, vol. 61, no. 10, pp. 1447–1453, 2012. View at Publisher · View at Google Scholar · View at Scopus
  73. N. K. Jacob, J. V. Cooley, T. N. Yee et al., “Identification of Sensitive Serum microRNA Biomarkers for Radiation Biodosimetry,” PLoS ONE, vol. 8, no. 2, Article ID e57603, 2013. View at Publisher · View at Google Scholar · View at Scopus
  74. G. J. Zhang, H. Zhou, H. X. Xiao, Y. Li, and T. Zhou, “MiR-378 is an independent prognostic factor and inhibits cell growth and invasion in colorectal cancer,” BMC Cancer, vol. 14, no. 1, p. 109, 2014. View at Google Scholar
  75. M. Sand, M. Skrygan, D. Georgas et al., “Microarray analysis of microRNA expression in cutaneous squamous cell carcinoma,” Journal of Dermatological Science, vol. 68, no. 3, pp. 119–126, 2012. View at Publisher · View at Google Scholar · View at Scopus
  76. S. Hauser, L. M. Wulfken, S. Holdenrieder et al., “Analysis of serum microRNAs (miR-26a-2*, miR-191, miR-337-3p and miR-378) as potential biomarkers in renal cell carcinoma,” Cancer Epidemiology, vol. 36, no. 4, pp. 391–394, 2012. View at Publisher · View at Google Scholar · View at Scopus
  77. L. S. Mangala, Y. Zhang, Z. He et al., “Effects of simulated microgravity on expression profile of microRNA in human lymphoblastoid cells,” The Journal of Biological Chemistry, vol. 286, no. 37, pp. 32483–32490, 2011. View at Publisher · View at Google Scholar · View at Scopus
  78. P. Alexiou, M. Maragkakis, G. L. Papadopoulos, M. Reczko, and A. G. Hatzigeorgiou, “Lost in translation: an assessment and perspective for computational microrna target identification,” Bioinformatics, vol. 25, no. 23, pp. 3049–3055, 2009. View at Publisher · View at Google Scholar · View at Scopus
  79. J. Nunez-Iglesias, C.-C. Liu, T. E. Morgan, C. E. Finch, and X. J. Zhou, “Joint genome-wide profiling of miRNA and mRNA expression in Alzheimer's disease cortex reveals altered miRNA regulation,” PLoS ONE, vol. 5, no. 2, Article ID e8898, 2010. View at Publisher · View at Google Scholar · View at Scopus
  80. L. Ma, Y. Huang, W. Zhu et al., “An integrated analysis of miRNA and mRNA expressions in non-small cell lung cancers,” PLoS ONE, vol. 6, no. 10, Article ID e26502, 2011. View at Publisher · View at Google Scholar · View at Scopus
  81. J. C. Engelmann and R. Spang, “A least angle regression model for the prediction of canonical and non-canonical miRNA-mRNA interactions,” PLoS ONE, vol. 7, no. 7, Article ID e40634, 2012. View at Publisher · View at Google Scholar · View at Scopus
  82. N. Bossel Ben-Moshe, R. Avraham, M. Kedmi et al., “Context-specific microRNA analysis: identification of functional microRNAs and their mRNA targets,” Nucleic Acids Research, vol. 40, no. 21, pp. 10614–10627, 2012. View at Publisher · View at Google Scholar · View at Scopus
  83. S. Artmann, K. Jung, A. Bleckmann, and T. Beißbarth, “Detection of simultaneous group effects in microRNA expression and related target gene sets,” PLoS ONE, vol. 7, no. 6, Article ID e38365, 2012. View at Publisher · View at Google Scholar · View at Scopus
  84. R. N. Germain, “MHC-dependent antigen processing and peptide presentation: providing ligands for T lymphocyte activation,” Cell, vol. 76, no. 2, pp. 287–299, 1994. View at Publisher · View at Google Scholar · View at Scopus
  85. I. V. Konstantinova, E. N. Antropova, V. I. Legenkov, and V. D. Zazhirey, “Study of the reactivity of blood lymphoid cells in crew members of Soyuz 6, 7 and 8 before and after space flight,” Kosmicheskaia Biologiia i Meditsina, vol. 7, no. 6, pp. 35–40, 1973 (Russian). View at Google Scholar · View at Scopus
  86. A. Cogoli and A. Tschopp, “Lymphocyte reactivity during spaceflight,” Immunology Today, vol. 6, no. 1, pp. 1–4, 1985. View at Google Scholar · View at Scopus
  87. N. Guéguinou, C. Huin-Schohn, M. Bascove et al., “Could spaceflight-associated immune system weakening preclude the expansion of human presence beyond Earth's orbit?” Journal of Leukocyte Biology, vol. 86, no. 5, pp. 1027–1038, 2009. View at Publisher · View at Google Scholar · View at Scopus
  88. Y. O. Nunez, J. M. Truitt, G. Gorini et al., “Positively correlated miRNA-mRNA regulatory networks in mouse frontal cortex during early stages of alcohol dependence,” BMC Genomics, vol. 14, p. 725, 2013. View at Google Scholar
  89. R. P. Sullivan, L. A. Fogel, J. W. Leong et al., “MicroRNA-155 tunes both the threshold and extent of NK cell activation via targeting of multiple signaling pathways,” The Journal of Immunology, vol. 191, no. 12, pp. 5904–5913, 2013. View at Publisher · View at Google Scholar
  90. F. Gao, Z.-L. Zhao, W.-T. Zhao et al., “MiR-9 modulates the expression of interferon-regulated genes and MHC class I molecules in human nasopharyngeal carcinoma cells,” Biochemical and Biophysical Research Communications, vol. 431, no. 3, pp. 610–616, 2013. View at Publisher · View at Google Scholar · View at Scopus
  91. F. Bazzoni, M. Rossato, M. Fabbri et al., “Induction and regulatory function of miR-9 in human monocytes and neutrophils exposed to proinflammatory signals,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 13, pp. 5282–5287, 2009. View at Publisher · View at Google Scholar · View at Scopus
  92. S. Thiele, J. Wittmann, H.-M. Jäck, and A. Pahl, “miR-9 enhances IL-2 production in activated human CD4+ T cells by repressing Blimp-1,” European Journal of Immunology, vol. 42, no. 8, pp. 2100–2108, 2012. View at Publisher · View at Google Scholar · View at Scopus
  93. M. Singh, F. Del carpio-Cano, J. Y. Belcher et al., “Functional roles of osteoactivin in normal and disease processes,” Critical Reviews in Eukaryotic Gene Expression, vol. 20, no. 4, pp. 341–357, 2010. View at Google Scholar · View at Scopus
  94. M. Cogoli-Greuter, M. A. Meloni, L. Sciola et al., “Movements and interactions of leukocytes in microgravity,” Journal of Biotechnology, vol. 47, no. 2-3, pp. 279–287, 1996. View at Publisher · View at Google Scholar · View at Scopus
  95. I. Walther, P. Pippia, M. A. Meloni, F. Turrini, F. Mannu, and A. Cogoli, “Simulated microgravity inhibits the genetic expression of interleukin-2 and its receptor in mitogen-activated T lymphocytes,” FEBS Letters, vol. 436, no. 1, pp. 115–118, 1998. View at Publisher · View at Google Scholar · View at Scopus
  96. X. Ma, J. Pietsch, M. Wehland et al., “Differential gene expression profile and altered cytokine secretion of thyroid cancer cells in space,” The FASEB Journal, vol. 28, no. 2, pp. 813–835, 2014. View at Google Scholar
  97. D. Chang, H. Xu, Y. Guo et al., “Simulated microgravity alters the metastatic potential of a human lung adenocarcinoma cell line,” In Vitro Cellular and Developmental Biology—Animal, vol. 49, no. 3, pp. 170–177, 2013. View at Publisher · View at Google Scholar · View at Scopus
  98. S. Hong, X. Li, Y. Zhao, Q. Yang, and B. Kong, “53BP1 suppresses tumor growth and promotes susceptibility to apoptosis of ovarian cancer cells through modulation of the Akt pathway,” Oncology Reports, vol. 27, no. 4, pp. 1251–1257, 2012. View at Publisher · View at Google Scholar · View at Scopus