Molykutty J Aryankalayil1, Shannon Martello2, Michelle A Bylicky2, Sunita Chopra2, Jared M May2, Aman Shankardass2, Laurel MacMillan3, Landy Sun3, Jaleal Sanjak3, Claire Vanpouille-Box4, Iris Eke2,5, C Norman Coleman2,6. 1. Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Room B3B406, Bethesda, MD, 20892, USA. aryankalayilm@mail.nih.gov. 2. Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Room B3B406, Bethesda, MD, 20892, USA. 3. Gryphon Scientific, Takoma Park, MD, 20912, USA. 4. Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, 10065, USA. 5. Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, 94305, USA. 6. Radiation Research Program, National Cancer Institute, National Institutes of Health, Rockville, MD, 20850, USA.
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.
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.
Authors: Paul A Heidenreich; Ingela Schnittger; H William Strauss; Randall H Vagelos; Byron K Lee; Carol S Mariscal; David J Tate; Sandra J Horning; Richard T Hoppe; Steven L Hancock Journal: J Clin Oncol Date: 2007-01-01 Impact factor: 44.544
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