The Influence of microRNA on Signaling Pathways Activity in Radiosensitive and Radioresistant Cancer Cell Lines after Radiation Exposure

Maslennikova D.A., Khokhlova A.V., Pogodina E.S., Zazhoma D.A., Vorsina S.N., Beloborodov E.A., Saenko V.V., Saenko Y.V.

Key words: microRNA; hsa-miR-590-3p; gene expression; cancer cell radiosensitivity; gamma radiation; Integrin signaling pathway; General transcription by RNA polymerase I.

2017, volume 9, issue 2, page 29.

DOI: https://doi.org/10.17691/stm2017.9.2.03

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The aim of the investigation was to study microRNA expression and its influence on signaling pathways activity in radioresistant and radiosensitive cell lines exposed to radiation.

Materials and Methods. Radioresistant K562 cell line and radiosensitive HL-60 and Raji cell lines were used in the study. Cell survival was estimated after exposure to 4 Gy gamma radiation. MicroRNA composition was studied 1, 4 and 24 h after radiation exposure using massively parallel sequencing method. Bioinformatics analysis was performed using GenXpro and PANTHER database.

Results. After single 4 Gy radiation exposure, the number of cells with the signs of necrosis increased several times in radiosensitive cell lines as compared to control samples. MicroRNA hsa-miR-590-3p was found in each studied cell line at every stage of the experiment. The most significant differences between radioresistant and radiosensitive cell lines were observed in dynamics of microRNA influence on Integrin signaling pathway and General transcription by RNA polymerase I pathway.

Conclusion. MicroRNA hsa-miR-590-3p dynamics and expression level were found to correlate with cancer cell radiosensitivity. Its influence on radioresistant and radiosensitive cell lines was different: in radioresistant K562 cell line, the inhibitory effect of microRNA on Integrin signaling pathway was reduced and this effect on General transcription by RNA polymerase I pathway was increased.

Guo L., Xiao Y., Fan M., Li J., Wang Y. Profiling global kinome signatures of the radioresistant MCF-7/C6 breast cancer cells using MRM-based targeted proteomics. J Proteome Res 2015; 14(1): 193–201, https://doi.org/10.1021/pr500919w.
Kim W.-Y., Oh S.H., Woo J.-K., Hong W.K., Lee H.-Y. Targeting heat shock protein 90 overrides the resistance of lung cancer cells by blocking radiation-induced stabilization of hypoxia-inducible factor-1alpha. Cancer Res 2009; 69(4): 1624–1632, https://doi.org/10.1158/0008-5472.can-08-0505.
Tang Y., Cui Y., Li Z., Jiao Z., Zhang Y., He Y., Chen G., Zhou Q., Wang W., Zhou X., Luo J., Zhang S. Radiation-induced miR-208a increases the proliferation and radioresistance by targeting p21 in human lung cancer cells. J Exp Clin Cancer Res 2016; 35: 7, https://doi.org/10.1186/s13046-016-0285-3.
Li J.Y., Li Y.Y., Jin W., Yang Q., Shao Z.M., Tian X.S. ABT-737 reverses the acquired radioresistance of breast cancer cells by targeting Bcl-2 and Bcl-xL. J Exp Clin Cancer Res 2012; 31: 102, https://doi.org/10.1186/1756-9966-31-102.
Filipowicz W., Bhattacharyya S.N., Sonenberg N. Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat Rev Genet 2008; 9(2): 102–114, https://doi.org/10.1038/nrg2290.
Zheng L., Zhang Y., Liu Y., Zhou M., Lu Y., Yuan L., Zhang C., Hong M., Wang S., Li X. MiR-106b induces cell radioresistance via the PTEN/PI3K/AKT pathways and p21 in colorectal cancer. J Transl Med 2015; 13: 252, https://doi.org/10.1186/s12967-015-0592-z.
Ma R., Jiang T., Kang X. Circulating microRNAs in cancer: origin, function and application. J Exp Clin Cancer Res 2012; 31: 38–47, https://doi.org/10.1186/1756-9966-31-38.
Suzuki H., Maruyama R., Yamamoto E., Kai M. Epigenetic alteration and microRNA dysregulation in cancer. Front Genet 2013; 4: 258, https://doi.org/10.3389/fgene.2013.00258.
Drakaki A., Iliopoulos D. MicroRNA-gene signaling pathways in pancreatic cancer. Biomed J 2013; 36(5): 200–208, https://doi.org/10.4103/2319-4170.119690.
Metheetrairut C., Slack F.J. MicroRNAs in the ionizing radiation response and in radiotherapy. Curr Opin Genet Dev 2013; 23(1): 12–19, https://doi.org/10.1016/j.gde.2013.01.002.
Li G., Qiu Y., Su Z., Ren S., Liu C., Tian Y., Liu Y. Genome-wide analyses of radioresistance-associated miRNA expression profile in nasopharyngeal carcinoma using next generation deep sequencing. PLoS One 2013; 8(12): e84486, https://doi.org/10.1371/journal.pone.0084486.
Zhang B., Chen J., Ren Z., Chen Y., Li J., Miao X., Song Y., Zhao T., Li Y., Shi Y., Ren D., Liu J. A specific miRNA signature promotes radioresistance of human cervical cancer cells. Cancer Cell Int 2013; 13(1): 118, https://doi.org/10.1186/1475-2867-13-118.
Su H., Jin X., Zhang X., Xue S., Deng X., Shen L., Fang Y., Xie C. Identification of microRNAs involved in the radioresistance of esophageal cancer cells. Cell Biology Int 2014; 38(3): 318–325, https://doi.org/10.1002/cbin.10202.
Qu C., Liang Z., Huang J., Zhao R., Su C., Wang S., Wang X., Zhang R., Lee M.H., Yang H. MiR-205 determines the radioresistance of human nasopharyngeal carcinoma by directly targeting PTEN. Cell Cycle 2012; 11(4): 785–796, https://doi.org/10.4161/cc.11.4.19228.
Mascotti K., McCullough J., Burger S.R. HPC viability measurement: trypan blue versus acridine orange and propidium iodide. Transfusion 2000; 40(6): 693–696, https://doi.org/10.1046/j.1537-2995.2000.40060693.x.
Müller S., Rycak L., Winter P., Kahl G., Koch I., Rotter B. omiRas: a Web server for differential expression analysis of miRNAs derived from small RNA-Seq data. Bioinformatics 2013; 29(20): 2651–2652, https://doi.org/10.1093/bioinformatics/btt457.
Wang J., Le T., Wei R., Jiao Y. Knockdown of JMJD1C, a target gene of hsa-miR-590-3p, inhibits mitochondrial dysfunction and oxidative stress in MPP+-treated MES23.5 and SH-SY5Y cells. Cell Mol Biol 2016; 62(3): 39–45.
Villa C., Fenoglio C., De Riz M., Clerici F., Marcone A., Benussi L., Ghidoni R., Gallone S., Cortini F., Serpente M., Cantoni C., Fumagalli G., Martinelli Boneschi F., Cappa S., Binetti G., Franceschi M., Rainero I., Giordana M.T., Mariani C., Bresolin N., Scarpini E., Galimberti D. Role of hnRNP-A1 and miR-590-3p in neuronal death: genetics and expression analysis in patients with Alzheimer disease and frontotemporal lobar degeneration. Rejuvenation Res 2011; 14(3): 275–281, https://doi.org/10.1089/rej.2010.1123.
Vaishnavi V., Manikandan M., Tiwary B.K., Munirajan A.K. Insights on the functional impact of microRNAs present in autism-associated copy number variants. PLoS One 2013; 8(2): e56781, https://doi.org/10.1371/journal.pone.0056781.
Spencer P., Fry R.C., Kisby G.E. Unraveling 50-year-old clues linking neurodegeneration and cancer to cycad toxins: are microRNAs common mediators? Front Genet 2012; 3: 192, https://doi.org/10.3389/fgene.2012.00192.
Chen M., Zhu N., Liu X., Laurent B., Tang Z., Eng R., Shi Y., Armstrong S.A., Roeder R.G. JMJD1C is required for the survival of acute myeloid leukemia by functioning as a coactivator for key transcription factors. Genes Dev 2015; 29(20): 2123–2139, https://doi.org/10.1101/gad.267278.115.
Zhu N., Chen M., Eng R., DeJong J., Sinha A.U., Rahnamay N.F., Koche R., Al-Shahrour F., Minehart J.C., Chen C.W., Deshpande A.J., Xu H., Chu S.H., Ebert B.L., Roeder R.G., Armstrong S.A. MLL-AF9- and HOXA9-mediated acute myeloid leukemia stem cell self-renewal requires JMJD1C. J Clin Invest 2016; 126(3): 997–1011, https://doi.org/10.1172/jci82978.
Desgrosellier J.S., Cheresh D.A. Integrins in cancer: biological implications and therapeutic opportunities. Nat Rev Cancer 2010; 10(1): 9–22, https://doi.org/10.1038/nrc2748.
Cordes N., Seidler J., Durzok R., Geinitz H., Brakebusch C. β1-integrin-mediated signaling essentially contributes to cell survival after radiation-induced genotoxic injury. Oncogene 2006; 25(9): 1378–1390, https://doi.org/10.1038/sj.onc.1209164.
Eke I., Deuse Y., Hehlgans S., Gurtner K., Krause M., Baumann M., Shevchenko A., Sandfort V., Cordes N. β1 integrin/FAK/cortactin signaling is essential for human head and neck cancer resistance to radiotherapy. J Clin Invest 2012; 122(4): 1529–1540, https://doi.org/10.1172/jci61350.
Bywater M.J., Poortinga G., Sanij E., Hein N., Peck A., Cullinane C., Wall M., Cluse L., Drygin D., Anderes K., Huser N., Proffitt C., Bliesath J., Haddach M., Schwaebe M.K., Ryckman D.M., Rice W.G., Schmitt C., Lowe S.W., Johnstone R.W., Pearson R.B., McArthur G.A., Hannan R.D. Inhibition of RNA polymerase I as a therapeutic strategy to promote cancer-specific activation of p53. Cancer Cell 2012; 22(1): 51–65, https://doi.org/10.1016/j.ccr.2012.05.019.

Maslennikova D.A., Khokhlova A.V., Pogodina E.S., Zazhoma D.A., Vorsina S.N., Beloborodov E.A., Saenko V.V., Saenko Y.V. The Influence of microRNA on Signaling Pathways Activity in Radiosensitive and Radioresistant Cancer Cell Lines after Radiation Exposure. Sovremennye tehnologii v medicine 2017; 9(2): 29, https://doi.org/10.17691/stm2017.9.2.03