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Open Access 01-12-2021 | Biomarkers | Research

Analysis of lncRNA-miRNA-mRNA expression pattern in heart tissue after total body radiation in a mouse model

Authors: Molykutty J. Aryankalayil, Shannon Martello, Michelle A. Bylicky, Sunita Chopra, Jared M. May, Aman Shankardass, Laurel MacMillan, Landy Sun, Jaleal Sanjak, Claire Vanpouille-Box, Iris Eke, C. Norman Coleman

Published in: Journal of Translational Medicine | Issue 1/2021

Abstract

Background

Radiation therapy is integral to effective thoracic cancer treatments, but its application is limited by sensitivity of critical organs such as the heart. The impacts of acute radiation-induced damage and its chronic effects on normal heart cells are highly relevant in radiotherapy with increasing lifespans of patients. Biomarkers for normal tissue damage after radiation exposure, whether accidental or therapeutic, are being studied as indicators of both acute and delayed effects. Recent research has highlighted the potential importance of RNAs, including messenger RNAs (mRNAs), microRNAs (miRNAs), and long non-coding RNAs (lncRNAs) as biomarkers to assess radiation damage. Understanding changes in mRNA and non-coding RNA expression will elucidate biological pathway changes after radiation.

Methods

To identify significant expression changes in mRNAs, lncRNAs, and miRNAs, we performed whole transcriptome microarray analysis of mouse heart tissue at 48 h after whole-body irradiation with 1, 2, 4, 8, and 12 Gray (Gy). We also validated changes in specific lncRNAs through RT-qPCR. Ingenuity Pathway Analysis (IPA) was used to identify pathways associated with gene expression changes.

Results

We observed sustained increases in lncRNAs and mRNAs, across all doses of radiation. Alas2, Aplnr, and Cxc3r1 were the most significantly downregulated mRNAs across all doses. Among the significantly upregulated mRNAs were cell-cycle arrest biomarkers Gdf15, Cdkn1a, and Ckap2. Additionally, IPA identified significant changes in gene expression relevant to senescence, apoptosis, hemoglobin synthesis, inflammation, and metabolism. LncRNAs Abhd11os, Pvt1, Trp53cor1, and Dino showed increased expression with increasing doses of radiation. We did not observe any miRNAs with sustained up- or downregulation across all doses, but miR-149-3p, miR-6538, miR-8101, miR-7118-5p, miR-211-3p, and miR-3960 were significantly upregulated after 12 Gy.

Conclusions

Radiation-induced RNA expression changes may be predictive of normal tissue toxicities and may indicate targetable pathways for radiation countermeasure development and improved radiotherapy treatment plans.

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Dracham CB, Shankar A, Madan R. Radiation induced secondary malignancies: a review article. Radiat Oncol J. 2018;36:85–94. https://doi.org/10.3857/roj.2018.00290.CrossRefPubMedPubMedCentral

Darby S, McGale P, Peto R, Granath F, Hall P, Ekbom A. Mortality from cardiovascular disease more than 10 years after radiotherapy for breast cancer: nationwide cohort study of 90 000 Swedish women. Br Med J. 2003;326:256–7. https://doi.org/10.1136/bmj.326.7383.256.CrossRef

Desai MY, Jellis CL, Kotecha R, Johnston DR, Griffin BP. Radiation-associated cardiac disease: a practical approach to diagnosis and management. JACC Cardiovasc Imaging. 2018;11:1132–49. https://doi.org/10.1016/j.jcmg.2018.04.028.CrossRefPubMed

Denham JW, Hauer-Jensen M. The radiotherapeutic injury—a complex “wound.” Radiother Oncol. 2002;63:129–45. https://doi.org/10.1016/S0167-8140(02)00060-9.CrossRefPubMed

Shimizu Y, Kodama K, Nishi N, Kasagi F, Suyama A, Soda M, et al. Radiation exposure and circulatory disease risk: Hiroshima and Nagasaki atomic bomb survivor data, 1950–2003. BMJ. 2010;340:193. https://doi.org/10.1136/bmj.b5349.CrossRef

Shimizu Y, Pierce DA, Preston DL, Mabuchi K. Studies of the mortality of atomic bomb survivors. Report 12, part II. Noncancer mortality: 1950–1990. Radiat Res. 1999;152:374–89. https://doi.org/10.2307/3580222.CrossRefPubMed

Preston DL, Shimizu Y, Pierce DA, Suyama A, Mabuchi K. Studies of mortality of atomic bomb survivors. Report 13: solid cancer and noncancer disease mortality: 1950–1997. Radiat Res. 2003;160:381–407. https://doi.org/10.1667/RR3049.CrossRefPubMed

Kashcheev VV, Chekin SY, Karpenko SV, Maksioutov MA, Menyaylo AN, Tumanov KA, et al. Radiation risk of cardiovascular diseases in the cohort of russian emergency workers of the chernobyl accident. Health Phys. 2017;113:23–9. https://doi.org/10.1097/HP.0000000000000670.CrossRefPubMed

Sardaro A, Petruzzelli MF, D’Errico MP, Grimaldi L, Pili G, Portaluri M. Radiation-induced cardiac damage in early left breast cancer patients: risk factors, biological mechanisms, radiobiology, and dosimetric constraints. Radiother Oncol. 2012;103:133–42. https://doi.org/10.1016/j.radonc.2012.02.008.CrossRefPubMed

10.

Heidenreich PA, Schnittger I, Strauss HW, Vagelos RH, Lee BK, Mariscal CS, et al. Screening for coronary artery disease after mediastinal irradiation for Hodgkin’s disease. J Clin Oncol. 2007;25:43–9. https://doi.org/10.1200/JCO.2006.07.0805.CrossRefPubMed

11.

Cella L, Oh JH, Deasy JO, Palma G, Liuzzi R, D’Avino V, et al. Predicting radiation-induced valvular heart damage. Acta Oncol (Madr). 2015;54:1796–804. https://doi.org/10.3109/0284186X.2015.1016624.CrossRef

12.

Cuzick J, Stewart H, Rutqvist L, Houghton J, Edwards R, Redmond C, et al. Cause-specific mortality in long-term survivors of breast cancer who participated in trials of radiotherapy. J Clin Oncol. 1994;12:447–53. https://doi.org/10.1200/JCO.1994.12.3.447.CrossRefPubMed

13.

Ping Z, Peng Y, Lang H, Xinyong C, Zhiyi Z, Xiaocheng W, et al. Oxidative stress in radiation-induced cardiotoxicity. Oxid Med Cell Longev. 2020. https://doi.org/10.1155/2020/3579143.CrossRefPubMedPubMedCentral

14.

De Moor JS, Mariotto AB, Parry C, Alfano CM, Padgett L, Kent EE, et al. Cancer survivors in the united states: prevalence across the survivorship trajectory and implications for care. Cancer Epidemiol Biomarkers Prev. 2013;22:561–70. https://doi.org/10.1158/1055-9965.EPI-12-1356.CrossRefPubMedPubMedCentral

15.

Curigliano G, Cardinale D, Dent S, Criscitiello C, Aseyev O, Lenihan D, et al. Cardiotoxicity of anticancer treatments: epidemiology, detection, and management. CA Cancer J Clin. 2016;66:309–25. https://doi.org/10.3322/caac.21341.CrossRefPubMed

16.

Gujral DM, Lloyd G, Bhattacharyya S. Radiation-induced valvular heart disease. Heart. 2016;102:269–76. https://doi.org/10.1136/heartjnl-2015-308765.CrossRefPubMed

17.

Stewart FA, Seemann I, Hoving S, Russell NS. Understanding radiation-induced cardiovascular damage and strategies for intervention. Clin Oncol. 2013;25:617–24. https://doi.org/10.1016/j.clon.2013.06.012.CrossRef

18.

Maraldo MV, Giusti F, Vogelius IR, Lundemann M, van der Kaaij MAE, Ramadan S, et al. Cardiovascular disease after treatment for Hodgkin’s lymphoma: an analysis of nine collaborative EORTC-LYSA trials. Lancet Haematol. 2015;2:e492-502. https://doi.org/10.1016/S2352-3026(15)00153-2.CrossRefPubMed

19.

Kuo AH, Ancukiewicz M, Kozak KR, Yock TI, Padera TP. Cardiac and inflammatory biomarkers do not correlate with volume of heart or lung receiving radiation. Radiat Oncol. 2015. https://doi.org/10.1186/s13014-014-0324-1.CrossRefPubMedPubMedCentral

20.

Dicarlo AL, Tamarat R, Rios CI, Benderitter M, Czarniecki CW, Allio TC, et al. Cellular therapies for treatment of radiation injury: report from a NIH/NIAID and IRSN workshop. Radiat Res. 2017;188:e54-75. https://doi.org/10.1667/RR14810.1.CrossRefPubMedPubMedCentral

21.

Slezak J, Kura B, Babal P, Barancik M, Ferko M, Frimmel K, et al. Potential markers and metabolic processes involved in the mechanism of radiation-induced heart injury. Can J Physiol Pharmacol. 2017;95:1190–203. https://doi.org/10.1139/cjpp-2017-0121.CrossRefPubMed

22.

Azimzadeh O, Azizova T, Merl-Pham J, Subramanian V, Bakshi MV, Moseeva M, et al. A dose-dependent perturbation in cardiac energy metabolism is linked to radiation-induced ischemic heart disease in Mayak nuclear workers. Oncotarget. 2017;8:9067–78. https://doi.org/10.18632/oncotarget.10424.CrossRefPubMed

23.

Zhang Y, Luo G, Zhang Y, Zhang M, Zhou J, Gao W, et al. Critical effects of long non-coding RNA on fibrosis diseases. Exp Mol Med. 2018;50:428. https://doi.org/10.1038/emm.2017.223.CrossRef

24.

Vliegenthart ADB, Shaffer JM, Clarke JI, Peeters LEJ, Caporali A, Bateman DN, et al. Comprehensive microRNA profiling in acetaminophen toxicity identifies novel circulating biomarkers for human liver and kidney injury. Sci Rep. 2015. https://doi.org/10.1038/srep15501.CrossRefPubMedPubMedCentral

25.

Matkovich SJ, Edwards JR, Grossenheider TC, De Guzman SC, Dorn GW. Epigenetic coordination of embryonic heart transcription by dynamically regulated long noncoding RNAs. Proc Natl Acad Sci USA. 2014;111:12264–9. https://doi.org/10.1073/pnas.1410622111.CrossRefPubMedPubMedCentral

26.

Ounzain S, Micheletti R, Beckmann T, Schroen B, Alexanian M, Pezzuto I, et al. Genome-wide profiling of the cardiac transcriptome after myocardial infarction identifies novel heart-specific long non-coding RNAs. Eur Heart J. 2015;36:353–68. https://doi.org/10.1093/eurheartj/ehu180.CrossRefPubMed

27.

Yang KC, Yamada KA, Patel AY, Topkara VK, George I, Cheema FH, et al. Deep RNA sequencing reveals dynamic regulation of myocardial noncoding RNAs in failing human heart and remodeling with mechanical circulatory support. Circulation. 2014;129:1009–21. https://doi.org/10.1161/CIRCULATIONAHA.113.003863.CrossRefPubMedPubMedCentral

28.

Sallam T, Sandhu J, Tontonoz P. Long noncoding RNA discovery in cardiovascular disease: decoding form to function. Circ Res. 2018;122:155–66. https://doi.org/10.1161/CIRCRESAHA.117.311802.CrossRefPubMedPubMedCentral

29.

Zangrando J, Zhang L, Vausort M, Maskali F, Marie PY, Wagner DR, et al. Identification of candidate long non-coding RNAs in response to myocardial infarction. BMC Genomics. 2014. https://doi.org/10.1186/1471-2164-15-460.CrossRefPubMedPubMedCentral

30.

Lin F, Gong X, Yu P, Yue A, Meng Q, Zheng L, et al. Distinct circulating expression profiles of long noncoding RNAs in heart failure patients with ischemic and nonischemic dilated cardiomyopathy. Front Genet. 2019. https://doi.org/10.3389/fgene.2019.01116.CrossRefPubMedPubMedCentral

31.

Poller W, Dimmeler S, Heymans S, Zeller T, Haas J, Karakas M, et al. Non-coding RNAs in cardiovascular diseases: diagnostic and therapeutic perspectives. Eur Heart J. 2018;39:2704–16. https://doi.org/10.1093/eurheartj/ehx165.CrossRefPubMed

32.

Papait R, Kunderfranco P, Stirparo GG, Latronico MVG, Condorelli G. Long noncoding RNA: a new player of heart failure? J Cardiovasc Transl Res. 2013;6:876–83. https://doi.org/10.1007/s12265-013-9488-6.CrossRefPubMedPubMedCentral

33.

Metheetrairut C, Slack FJ. MicroRNAs in the ionizing radiation response and in radiotherapy. Curr Opin Genet Dev. 2013;23:12–9. https://doi.org/10.1016/j.gde.2013.01.002.CrossRefPubMedPubMedCentral

34.

Wojciechowska A, Braniewska A, Kozar-Kamińska K. MicroRNA in cardiovascular biology and disease. Adv Clin Exp Med. 2017;26:865–74. https://doi.org/10.17219/acem/62915.CrossRefPubMed

35.

Wang K, Long B, Li N, Li L, Liu CY, Dong YH, et al. MicroRNA-2861 regulates programmed necrosis in cardiomyocyte by impairing adenine nucleotide translocase 1 expression. Free Radic Biol Med. 2016;91:58–67. https://doi.org/10.1016/j.freeradbiomed.2015.11.031.CrossRefPubMed

36.

Jakob P, Landmesser U. Role of microRNAs in stem/progenitor cells and cardiovascular repair. Cardiovasc Res. 2012;93:614–22. https://doi.org/10.1093/cvr/cvr311.CrossRefPubMed

37.

Zhang X, Mao H, Chen J, Wen S, Li D, Ye M, et al. Increased expression of microRNA-221 inhibits PAK1 in endothelial progenitor cells and impairs its function via c-Raf/MEK/ERK pathway. Biochem Biophys Res Commun. 2013;431:404–8. https://doi.org/10.1016/j.bbrc.2012.12.157.CrossRefPubMed

38.

Terradas M, Martín M, Repullès J, Huarte M, Genescà A. Distinct sets of lncRNAs are differentially modulated after exposure to high and low doses of X rays. Radiat Res. 2016;186:549–58. https://doi.org/10.1667/RR14377.1.CrossRefPubMed

39.

Nie J, Peng C, Pei W, Zhu W, Zhang S, Cao H, et al. A novel role of long non-coding RNAs in response to X-ray irradiation. Toxicol Vitr. 2015;30:536–44. https://doi.org/10.1016/j.tiv.2015.09.007.CrossRef

40.

Beer L, Nemec L, Wagner T, Ristl R, Altenburger LM, Ankersmit HJ, et al. Ionizing radiation regulates long non-coding RNAs in human peripheral blood mononuclear cells. J Radiat Res. 2017;58:201–9. https://doi.org/10.1093/jrr/rrw111.CrossRefPubMed

41.

Liang X, Zheng S, Cui J, Yu D, Yang G, Zhou L, et al. Alterations of MicroRNA expression in the liver, heart, and testis of mice upon exposure to repeated low-dose radiation. Dose Response. 2018. https://doi.org/10.1177/1559325818799561.CrossRefPubMedPubMedCentral

42.

Palayoor ST, John-Aryankalayil M, Makinde AY, Falduto MT, Magnuson SR, Coleman CN. Differential expression of stress and immune response pathway transcripts and miRNAs in normal human endothelial cells subjected to fractionated or single-dose radiation. Mol Cancer Res. 2014;12:1002–15. https://doi.org/10.1158/1541-7786.MCR-13-0623.CrossRefPubMedPubMedCentral

43.

Rogers CJ, Lukaszewicz AI, Yamada-Hanff J, Micewicz ED, Ratikan JA, Starbird MA, et al. Identification of miRNA signatures associated with radiation-induced late lung injury in mice. PLoS ONE. 2020. https://doi.org/10.1371/journal.pone.0232411.CrossRefPubMedPubMedCentral

44.

Aryankalayil MJ, Chopra S, Levin J, Eke I, Makinde A, Das S, et al. Radiation-induced long noncoding RNAs in a mouse model after whole-body irradiation. Radiat Res. 2018;189:251–63. https://doi.org/10.1667/RR14891.1.CrossRefPubMedPubMedCentral

45.

Bhattacharya S, Asaithamby A. Ionizing radiation and heart risks. Semin Cell Dev Biol. 2016;58:14–25. https://doi.org/10.1016/j.semcdb.2016.01.045.CrossRefPubMed

46.

Aryankalayil MJ, Chopra S, Makinde A, Eke I, Levin J, Shankavaram U, et al. Microarray analysis of miRNA expression profiles following whole body irradiation in a mouse model. Biomarkers. 2018;23:689–703. https://doi.org/10.1080/1354750X.2018.1479771.CrossRefPubMedPubMedCentral

47.

Schmitt AM, Garcia JT, Hung T, Flynn RA, Shen Y, Qu K, et al. An inducible long noncoding RNA amplifies DNA damage signaling. Nat Genet. 2016;48:1370–6. https://doi.org/10.1038/ng.3673.CrossRefPubMedPubMedCentral

48.

Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, et al. Limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015;43: e47. https://doi.org/10.1093/nar/gkv007.CrossRefPubMedPubMedCentral

49.

Ritchie ME, Silver J, Oshlack A, Holmes M, Diyagama D, Holloway A, et al. A comparison of background correction methods for two-colour microarrays. Bioinformatics. 2007;23:2700–7. https://doi.org/10.1093/bioinformatics/btm412.CrossRefPubMed

50.

Smyth GK. Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol. 2004. https://doi.org/10.2202/1544-6115.1027.CrossRefPubMed

51.

Aken BL, Ayling S, Barrell D, Clarke L, Curwen V, Fairley S, et al. The Ensembl gene annotation system. Database. 2016. https://doi.org/10.1093/database/baw093.CrossRefPubMedPubMedCentral

52.

Agarwal V, Bell GW, Nam JW, Bartel DP. Predicting effective microRNA target sites in mammalian mRNAs. Elife. 2015. https://doi.org/10.7554/eLife.05005.CrossRefPubMedPubMedCentral

53.

Lee WJ, Majumder ZR, Jeoung D, Lee HJ, Kim SH, Bae S, et al. Organ-specific gene expressions in C57BL/6 mice after exposure to low-dose radiation. Radiat Res. 2006;165:562–9. https://doi.org/10.1667/RR3549.1.CrossRefPubMed

54.

Zeng ZM, Du HY, Xiong L, Zeng XL, Zhang P, Cai J, et al. BRCA1 protects cardiac microvascular endothelial cells against irradiation by regulating p21-mediated cell cycle arrest. Life Sci. 2020. https://doi.org/10.1016/j.lfs.2020.117342.CrossRefPubMed

55.

Wang T, Liu J, McDonald C, Lupino K, Zhai X, Wilkins BJ, et al. GDF 15 is a heart-derived hormone that regulates body growth. EMBO Mol Med. 2017;9:1150–64. https://doi.org/10.15252/emmm.201707604.CrossRefPubMedPubMedCentral

56.

Park H, Kim CH, Jeong JH, Park M, Kim KS. GDF15 contributes to radiation-induced senescence through the ros-mediated p16 pathway in human endothelial cells. Oncotarget. 2016;7:9634–44. https://doi.org/10.18632/oncotarget.7457.CrossRefPubMedPubMedCentral

57.

Kyung UH, Kim E, Bae CD, Park J. TMAP/CKAP2 is essential for proper chromosome segregation. Cell Cycle. 2009;8:314–24. https://doi.org/10.4161/cc.8.2.7597.CrossRef

58.

Zhang S, Wang Y, Chen S, Li J. Silencing of cytoskeleton-associated protein 2 represses cell proliferation and induces cell cycle arrest and cell apoptosis in osteosarcoma cells. Biomed Pharmacother. 2018;106:1396–403. https://doi.org/10.1016/j.biopha.2018.07.104.CrossRefPubMed

59.

Sawicki KT, Shang M, Wu R, Chang HC, Khechaduri A, Sato T, et al. Increased heme levels in the heart lead to exacerbated ischemic injury. J Am Heart Assoc. 2015;4: e002272. https://doi.org/10.1161/JAHA.115.002272.CrossRefPubMedPubMedCentral

60.

Nie YH, Liu XD, Huang R, Xie DF, Yin WJ, Guan H, et al. Analysis of mRNA expression patterns in peripheral blood cells of 3 patients with cancer after the first fraction of 2 Gy irradiation: an integrated case report and systematic review. Dose Response. 2019. https://doi.org/10.1177/1559325819833474.CrossRefPubMedPubMedCentral

61.

Doğan A. Apelin receptor (Aplnr) signaling promotes fibroblast migration. Tissue Cell. 2019;56:98–106. https://doi.org/10.1016/j.tice.2019.01.003.CrossRefPubMed

62.

Sawane M, Kidoya H, Muramatsu F, Takakura N, Kajiya K. Apelin attenuates UVB-induced edema and inflammation by promoting vessel function. Am J Pathol. 2011;179:2691–7. https://doi.org/10.1016/j.ajpath.2011.08.024.CrossRefPubMedPubMedCentral

63.

Li C, He J, Zhong X, Gan H, Xia Y. CX3CL1/CX3CR1 axis contributes to angiotensin II-induced vascular smooth muscle cell proliferation and inflammatory cytokine production. Inflammation. 2018;41:824–34. https://doi.org/10.1007/s10753-018-0736-4.CrossRefPubMed

64.

Golbus JR, Stitziel NO, Zhao W, Xue C, Farrall M, Mcpherson R, et al. Common and rare genetic variation in CCR2, CCR5, or CX3CR1 and risk of atherosclerotic coronary heart disease and glucometabolic traits. Circ Cardiovasc Genet. 2016;9:250–8. https://doi.org/10.1161/CIRCGENETICS.115.001374.CrossRefPubMedPubMedCentral

65.

Debo RJ, Lees CJ, Dugan GO, Caudell DL, Michalson KT, Hanbury DB, et al. Late effects of total-body gamma irradiation on cardiac structure and function in male rhesus macaques. Radiat Res. 2016;186:55–64. https://doi.org/10.1667/RR14357.1.CrossRefPubMedPubMedCentral

66.

Farese AM, Cohen MV, Katz BP, Smith CP, Jackson W, Cohen DM, et al. A nonhuman primate model of the hematopoietic acute radiation syndrome plus medical management. Health Phys. 2012;103:367–82. https://doi.org/10.1097/HP.0b013e31825f75a7.CrossRefPubMed

67.

Plett PA, Sampson CH, Chua HL, Joshi M, Booth C, Gough A, et al. Establishing a murine model of the hematopoietic syndrome of the acute radiation syndrome. Health Phys. 2012;103:343–55. https://doi.org/10.1097/HP.0b013e3182667309.CrossRefPubMedPubMedCentral

68.

Hall J, Jeggo PA, West C, Gomolka M, Quintens R, Badie C, et al. Ionizing radiation biomarkers in epidemiological studies—an update. Mutat Res Mutat Res. 2017;771:59–84. https://doi.org/10.1016/j.mrrev.2017.01.001.CrossRef

69.

Coleman CN, Eke I, Makinde AY, Chopra S, Demaria S, Formenti SC, et al. Radiation-induced adaptive response: new potential for cancer treatment. Clin Cancer Res. 2020. https://doi.org/10.1158/1078-0432.ccr-20-0572.CrossRefPubMedPubMedCentral

70.

Karimian A, Ahmadi Y, Yousefi B. Multiple functions of p21 in cell cycle, apoptosis and transcriptional regulation after DNA damage. DNA Repair. 2016;42:63–71. https://doi.org/10.1016/j.dnarep.2016.04.008.CrossRefPubMed

71.

Tsuchihara K, Lapin V, Bakal C, Okada H, Brown L, Hirota-Tsuchihara M, et al. Ckap2 regulates aneuploidy, cell cycling, and cell death in a p53-dependent manner. Cancer Res. 2005;65:6685–91. https://doi.org/10.1158/0008-5472.CAN-04-4223.CrossRefPubMed

72.

Sándor N, Schilling-Tóth B, Kis E, Benedek A, Lumniczky K, Sáfrány G, et al. Growth Differentiation Factor-15 (GDF-15) is a potential marker of radiation response and radiation sensitivity. Mutat Res Toxicol Environ Mutagen. 2015;793:142–9. https://doi.org/10.1016/j.mrgentox.2015.06.009.CrossRef

73.

Rai R, Ghosh AK, Eren M, Mackie AR, Levine DC, Kim SY, et al. Downregulation of the apelinergic axis accelerates aging, whereas its systemic restoration improves the mammalian healthspan. Cell Rep. 2017;21:1471–80. https://doi.org/10.1016/j.celrep.2017.10.057.CrossRefPubMedPubMedCentral

74.

Shyamasundar S, Ong C, Yung LYL, Dheen ST, Bay BH. miR-128 regulates genes associated with inflammation and fibrosis of rat kidney cells in vitro. Anat Rec. 2018;301:913–21. https://doi.org/10.1002/ar.23763.CrossRef

75.

Principe DR, Diaz AM, Torres C, Mangan RJ, DeCant B, McKinney R, et al. TGFβ engages MEK/ERK to differentially regulate benign and malignant pancreas cell function. Oncogene. 2017;36:4336–48. https://doi.org/10.1038/onc.2016.500.CrossRefPubMedPubMedCentral

76.

Butz H, Likó I, Czirják S, Igaz P, Khan MM, Zivkovic V, et al. Down-regulation of Wee1 kinase by a specific subset of microRNA in human sporadic pituitary adenomas. J Clin Endocrinol Metab. 2010. https://doi.org/10.1210/jc.2010-0581.CrossRefPubMed

77.

Perez-Añorve IX, Gonzalez-De la Rosa CH, Soto-Reyes E, Beltran-Anaya FO, Del Moral-Hernandez O, Salgado-Albarran M, et al. New insights into radioresistance in breast cancer identify a dual function of miR-122 as a tumor suppressor and oncomiR. Mol Oncol. 2019;13:1249–67. https://doi.org/10.1002/1878-0261.12483.CrossRefPubMedPubMedCentral

78.

Lang X, Green MD, Wang W, Yu J, Choi JE, Jiang L, et al. Radiotherapy and immunotherapy promote tumoral lipid oxidation and ferroptosis via synergistic repression of SLC7A11. Cancer Discov. 2019;9:1673–85. https://doi.org/10.1158/2159-8290.CD-19-0338.CrossRefPubMedPubMedCentral

79.

Guard SE, Poss ZC, Ebmeier CC, Pagratis M, Simpson H, Taatjes DJ, et al. The nuclear interactome of DYRK1A reveals a functional role in DNA damage repair. Sci Rep. 2019;9:6539. https://doi.org/10.1038/s41598-019-42990-5.CrossRefPubMedPubMedCentral

80.

Xu XL, Jiang YH, Feng JG, Su D, Chen PC, Mao WM. MicroRNA-17, MicroRNA-18a, and MicroRNA-19a are prognostic indicators in esophageal squamous cell carcinoma. Ann Thorac Surg. 2014;97:1037–45. https://doi.org/10.1016/j.athoracsur.2013.10.042.CrossRefPubMed

81.

Li L, Shi B, Chen J, Li C, Wang S, Wang Z, et al. An E2F1/MiR-17-92 negative feedback loop mediates proliferation of mouse palatal mesenchymal cells. Sci Rep. 2017. https://doi.org/10.1038/s41598-017-05479-7.CrossRefPubMedPubMedCentral

82.

Sharma S, Munger K. Expression of the long noncoding RNA dino in human papillomavirus-positive cervical cancer cells reactivates the dormant TP53 tumor suppressor through ATM/CHK2 signaling. MBio. 2020;11:1–15. https://doi.org/10.1128/mBio.01190-20.CrossRef

83.

Shasha D, Harrison LB. Anemia treatment and the radiation oncologist: optimizing patient outcomes. Oncology. 2001;15:1486–91.PubMed

84.

Rowinska Z, Koeppel TA, Sanati M, Schelzig H, Jankowski J, Weber C, et al. Role of the CX3C chemokine receptor CX3CR1 in the pathogenesis of atherosclerosis after aortic transplantation. PLoS ONE. 2017. https://doi.org/10.1371/journal.pone.0170644.CrossRefPubMedPubMedCentral

85.

Krigsfeld GS, Sanzari JK, Kennedy AR. The effects of proton radiation on the prothrombin and partial thromboplastin times of irradiated ferrets. Int J Radiat Biol. 2012;88:327–34. https://doi.org/10.3109/09553002.2012.652727.CrossRefPubMedPubMedCentral

86.

Feng M, Normolle D, Pan CC, Dawson LA, Amarnath S, Ensminger WD, et al. Dosimetric analysis of radiation-induced gastric bleeding. Int J Radiat Oncol Biol Phys. 2012. https://doi.org/10.1016/j.ijrobp.2012.02.029.CrossRefPubMedPubMedCentral

87.

Jackson IL, Gurung G, Poirier Y, Gopalakrishnan M, Cohen EP, Shea-Donohue T, et al. A New Zealand white rabbit model of thrombocytopenia and coagulopathy following total body irradiation across the dose range to induce the hematopoietic-subsyndrome of acute radiation syndrome. Int J Radiat Biol. 2019. https://doi.org/10.1080/09553002.2019.1668981.CrossRef

88.

Cannon MV, van Gilst WH, de Boer RA. Emerging role of liver X receptors in cardiac pathophysiology and heart failure. Basic Res Cardiol. 2016;111:1–17. https://doi.org/10.1007/s00395-015-0520-7.CrossRef

89.

Munetsuna E, Hojo Y, Hattori M, Ishii H, Kawato S, Ishida A, et al. Retinoic acid stimulates 17β-estradiol and testosterone synthesis in rat hippocampal slice cultures. Endocrinology. 2009;150:4260–9. https://doi.org/10.1210/en.2008-1644.CrossRefPubMed

90.

Francelle L, Galvan L, Gaillard MC, Petit F, Bernay B, Guillermier M, et al. The striatal long noncoding RNA Abhd11os is neuroprotective against an N-terminal fragment of mutant huntingtin invivo. Neurobiol Aging. 2015;36:1601.e7-16. https://doi.org/10.1016/j.neurobiolaging.2014.11.014.CrossRef

91.

Zhao Y, Cao F, Yu X, Chen C, Meng J, Zhong R, et al. Linc-RAM is required for FGF2 function in regulating myogenic cell differentiation. RNA Biol. 2018;15:404–12. https://doi.org/10.1080/15476286.2018.1431494.CrossRefPubMedPubMedCentral

92.

Yu X, Zhang Y, Li T, Ma Z, Jia H, Chen Q, et al. Long non-coding RNA Linc-RAM enhances myogenic differentiation by interacting with MyoD. Nat Commun. 2017. https://doi.org/10.1038/ncomms14016.CrossRefPubMedPubMedCentral

93.

Megeney LA, Kablar B, Perry RLS, Ying C, May L, Rudnicki MA. Severe cardiomyopathy in mice lacking dystrophin and MyoD. Proc Natl Acad Sci USA. 1999;96:220–5. https://doi.org/10.1073/pnas.96.1.220.CrossRefPubMedPubMedCentral

94.

Yu YH, Hu ZY, Li MH, Li B, Wang ZM, Chen SL. Cardiac hypertrophy is positively regulated by long non-coding RNA PVT1. Int J Clin Exp Pathol. 2015;8:2582–9.PubMedPubMedCentral

95.

Wu D, Li Y, Zhang H, Hu X. Knockdown of Lncrna PVT1 enhances radiosensitivity in non-small cell lung cancer by sponging miR-195. Cell Physiol Biochem. 2017;42:2453–66. https://doi.org/10.1159/000480209.CrossRefPubMed

96.

He Y, Jing Y, Wei F, Tang Y, Yang L, Luo J, et al. Long non-coding RNA PVT1 predicts poor prognosis and induces radioresistance by regulating DNA repair and cell apoptosis in nasopharyngeal carcinoma. Cell Death Dis. 2018. https://doi.org/10.1038/s41419-018-0265-y.CrossRefPubMedPubMedCentral

97.

Zhao Y, Zhao J, Guo X, She J, Liu Y. Long non-coding RNA PVT1, A molecular sponge for miR-149, contributes aberrant metabolic dysfunction and inflammation in IL-1β-simulated osteoarthritic chondrocytes. 2018. Biosci Rep. https://doi.org/10.1042/BSR20180576.CrossRefPubMedPubMedCentral

98.

Zheng C, Xiao Y, Li Y, He D. Knockdown of long non-coding RNA PVT1 inhibits the proliferation of raji cells through cell cycle regulation. Oncol Lett. 2019;18:1225–34. https://doi.org/10.3892/ol.2019.10450.CrossRefPubMedPubMedCentral

99.

Xiong X, Yuan J, Zhang N, Zheng Y, Liu J, Yang M. Silencing of lncRNA PVT1 by miR-214 inhibits the oncogenic GDF15 signaling and suppresses hepatocarcinogenesis. Biochem Biophys Res Commun. 2020;521:478–84. https://doi.org/10.1016/j.bbrc.2019.10.137.CrossRefPubMed

100.

Creemers EE, Van Rooij E. Function and therapeutic potential of noncoding RNAs in cardiac fibrosis. Circ Res. 2016;118:108–18. https://doi.org/10.1161/CIRCRESAHA.115.305242.CrossRefPubMed

101.

Thum T, Gross C, Fiedler J, Fischer T, Kissler S, Bussen M, et al. MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature. 2008;456:980–4. https://doi.org/10.1038/nature07511.CrossRefPubMed

102.

Lang N, Wang C, Zhao J, Shi F, Wu T, Cao H. Long non-coding RNA BCYRN1 promotes glycolysis and tumor progression by regulating the miR-149/PKM2 axis in non-small-cell lung cancer. Mol Med Rep. 2020;21:1509–16. https://doi.org/10.3892/mmr.2020.10944.CrossRefPubMedPubMedCentral

103.

Kong Q, Qiu M. Long noncoding RNA SNHG15 promotes human breast cancer proliferation, migration and invasion by sponging miR-211-3p. Biochem Biophys Res Commun. 2018;495:1594–600. https://doi.org/10.1016/j.bbrc.2017.12.013.CrossRefPubMed

104.

Quan J, Pan X, He T, Lin C, Lai Y, Chen P, et al. Tumor suppressor miR-211-5p is associated with cellular migration, proliferation and apoptosis in renal cell carcinoma. Exp Ther Med. 2018;15:4019–28. https://doi.org/10.3892/etm.2018.5908.CrossRefPubMedPubMedCentral

105.

Xia ZY, Hoo Y, Xie PL, Tang SY, Luo XH, Liao EY, et al. Runx2/miR-3960/miR-2861 positive feedback loop is responsible for osteogenic transdifferentiation of vascular smooth muscle cells. Biomed Res Int. 2015;2015: 624037. https://doi.org/10.1155/2015/624037.CrossRefPubMedPubMedCentral

106.

Filopei J, Frishman W. Radiation-induced heart disease. Cardiol Rev. 2012;20:184–8. https://doi.org/10.1097/CRD.0b013e3182431c23.CrossRefPubMed

107.

Shen L, Li C, Zhang H, Qiu S, Fu T, Xu Y. Downregulation of miR-146a Contributes to cardiac dysfunction induced by the tyrosine kinase inhibitor sunitinib. Front Pharmacol. 2019. https://doi.org/10.3389/fphar.2019.00914.CrossRefPubMedPubMedCentral

108.

Wang X, Song C, Zhou X, Han X, Li J, Wang Z, et al. Mitochondria associated microRNA expression profiling of heart failure. Biomed Res Int. 2017. https://doi.org/10.1155/2017/4042509.CrossRefPubMedPubMedCentral

109.

Liang Y, Hou L, Li L, Li L, Zhu L, Wang Y, et al. Dichloroacetate restores colorectal cancer chemosensitivity through the p53/miR-149-3p/PDK2-mediated glucose metabolic pathway. Oncogene. 2020;39:469–85. https://doi.org/10.1038/s41388-019-1035-8.CrossRefPubMed

110.

Zheng S, Guo S, Sun G, Shi Y, Wei Z, Tang Y, et al. Gain of metabolic benefit with ablation of miR-149-3p from subcutaneous adipose tissue in diet-induced obese mice. Mol Ther. 2019;18:194–203. https://doi.org/10.1016/j.omtn.2019.07.024.CrossRef

111.

Pettersen IKN, Tusubira D, Ashrafi H, Dyrstad SE, Hansen L, Liu XZ, et al. Upregulated PDK4 expression is a sensitive marker of increased fatty acid oxidation. Mitochondrion. 2019;49:97–110. https://doi.org/10.1016/j.mito.2019.07.009.CrossRefPubMed

112.

Paredes F, Sheldon K, Lassègue B, Williams HC, Faidley EA, Benavides GA, et al. Poldip2 is an oxygen-sensitive protein that controls PDH and αKGDH lipoylation and activation to support metabolic adaptation in hypoxia and cancer. Proc Natl Acad Sci USA. 2018;115:1789–94. https://doi.org/10.1073/pnas.1720693115.CrossRefPubMedPubMedCentral

113.

Wang C, Yuan Y, Wu J, Zhao Y, Gao X, Chen Y, et al. Plin5 deficiency exacerbates pressure overload-induced cardiac hypertrophy and heart failure by enhancing myocardial fatty acid oxidation and oxidative stress. Free Radic Biol Med. 2019;141:372–82. https://doi.org/10.1016/j.freeradbiomed.2019.07.006.CrossRefPubMed

114.

Ellis JM, Bowman CE, Wolfgang MJ. Metabolic and tissue-specific regulation of Acyl-CoA metabolism. PLoS ONE. 2015. https://doi.org/10.1371/journal.pone.0116587.CrossRefPubMedPubMedCentral

115.

Franklin MP, Sathyanarayan A, Mashek DG. Acyl-CoA thioesterase 1 (ACOT1) regulates PPARα to couple fatty acid flux with oxidative capacity during fasting. Diabetes. 2017;66:2112–23. https://doi.org/10.2337/db16-1519.CrossRefPubMedPubMedCentral

116.

Xia C, Dong R, Chen C, Wang H, Wang DW. Cardiomyocyte specific expression of Acyl-coA thioesterase 1 attenuates sepsis induced cardiac dysfunction and mortality. Biochem Biophys Res Commun. 2015;468:533–40. https://doi.org/10.1016/j.bbrc.2015.10.078.CrossRefPubMed

117.

Chung KW, Lee EK, Lee MK, Oh GT, Yu BP, Chung HY. Impairment of PPARα and the fatty acid oxidation pathway aggravates renal fibrosis during aging. J Am Soc Nephrol. 2018;29:1223–37. https://doi.org/10.1681/ASN.2017070802.CrossRefPubMedPubMedCentral

118.

Wu CY, Satapati S, Gui W, Max Wynn R, Sharma G, Lou M, et al. A novel inhibitor of pyruvate dehydrogenase kinase stimulates myocardial carbohydrate oxidation in diet-induced obesity. J Biol Chem. 2018;293:9604–13. https://doi.org/10.1074/jbc.RA118.002838.CrossRefPubMedPubMedCentral

119.

Sung MM, Das SK, Levasseur J, Byrne NJ, Fung D, Kim TT, et al. Resveratrol treatment of mice with pressure-overload-induced heart failure improves diastolic function and cardiac energy metabolism. Circ Heart Fail. 2015;8:128–37. https://doi.org/10.1161/CIRCHEARTFAILURE.114.001677.CrossRefPubMed

120.

Chopra S, Moroni M, Martello S, Bylicky M, May J, Hritzo B, et al. Gene expression profiles from heart, lung and liver samples of total-body-irradiated minipigs: implications for predicting radiation-induced tissue toxicity. Radiat Res. 2020;194:411–30. https://doi.org/10.1667/RADE-20-00123.1.CrossRefPubMedPubMedCentral

121.

Pchejetski D, Foussal C, Alfarano C, Lairez O, Calise D, Guilbeau-Frugier C, et al. Apelin prevents cardiac fibroblast activation and collagen production through inhibition of sphingosine kinase 1. Eur Heart J. 2012;33:2360–9. https://doi.org/10.1093/eurheartj/ehr389.CrossRefPubMed

122.

Goidescu CM, Vida-Simiti LA. The apelin-APJ system in the evolution of heart failure. Clujul Med. 2015;88:3–8. https://doi.org/10.15386/cjmed-380.CrossRefPubMedPubMedCentral

123.

Budworth H, Snijders AM, Marchetti F, Mannion B, Bhatnagar S, Kwoh E, et al. DNA repair and cell cycle biomarkers of radiation exposure and inflammation stress in human blood. PLoS ONE. 2012;7: e48619. https://doi.org/10.1371/journal.pone.0048619.CrossRefPubMedPubMedCentral

124.

Ellisen LW, Ramsayer KD, Johannessen CM, Yang A, Beppu H, Minda K, et al. REDD1, a developmentally regulated transcriptional target of p63 and p53, links p63 to regulation of reactive oxygen species. Mol Cell. 2002;10:995–1005. https://doi.org/10.1016/S1097-2765(02)00706-2.CrossRefPubMed

125.

Drevytska T, Gonchar E, Okhai I, Lynnyk O, Mankovska I, Klionsky D, et al. The protective effect of Hif3a RNA interference and HIF-prolyl hydroxylase inhibition on cardiomyocytes under anoxia-reoxygenation. Life Sci. 2018;202:131–9. https://doi.org/10.1016/j.lfs.2018.04.021.CrossRefPubMed

126.

Laughlin GA, Barrett-Connor E, Criqui MH, Kritz-Silverstein D. The prospective association of serum insulin-like growth factor I (IGF-I) and IGF-binding protein-1 levels with all cause and cardiovascular disease mortality in older adults: The Rancho Bernardo Study. J Clin Endocrinol Metab. 2004;89:114–20. https://doi.org/10.1210/jc.2003-030967.CrossRefPubMed

127.

Filiano AN, Fathallah-Shaykh HM, Fiveash J, Gage J, Cantor A, Kharbanda S, et al. Gene expression analysis in radiotherapy patients and C57BL/6 mice as a measure of exposure to ionizing radiation. Radiat Res. 2011. https://doi.org/10.1667/RR2419.1.CrossRefPubMed

Title: Analysis of lncRNA-miRNA-mRNA expression pattern in heart tissue after total body radiation in a mouse model
Authors: Molykutty J. Aryankalayil
Shannon Martello
Michelle A. Bylicky
Sunita Chopra
Jared M. May
Aman Shankardass
Laurel MacMillan
Landy Sun
Jaleal Sanjak
Claire Vanpouille-Box
Iris Eke
C. Norman Coleman
Publication date: 01-12-2021
Publisher: BioMed Central
Keyword: Biomarkers
Published in: Journal of Translational Medicine / Issue 1/2021
Electronic ISSN: 1479-5876
DOI: https://doi.org/10.1186/s12967-021-02998-w

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