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

Journal of Translational Medicine

Claire Vanpouille-Box¹  Landy Sun²  Jaleal Sanjak²  Laurel MacMillan²  Michelle A. Bylicky³  Sunita Chopra³  Aman Shankardass³  Jared M. May³  Molykutty J. Aryankalayil³  Shannon Martello³  Iris Eke⁴  C. Norman Coleman⁵ 

[1] Department of Radiation Oncology, Weill Cornell Medicine, 10065, New York, NY, USA;Gryphon Scientific, 20912, Takoma Park, MD, USA;Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Room B3B406, 20892, Bethesda, MD, USA;Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Room B3B406, 20892, Bethesda, MD, USA;Department of Radiation Oncology, Stanford University School of Medicine, 94305, Stanford, CA, USA;Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Room B3B406, 20892, Bethesda, MD, USA;Radiation Research Program, National Cancer Institute, National Institutes of Health, 20850, Rockville, MD, USA;

关键词: Radiation;    Biomarkers;    Normal tissue injury;    miRNA;    mRNA;    lncRNA;    Heart;   

DOI  :  10.1186/s12967-021-02998-w

来源: Springer

【 摘 要 】

BackgroundRadiation 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.MethodsTo 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.ResultsWe 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.ConclusionsRadiation-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.

【 授权许可】

CC BY