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Title: Comparative RNA-Seq transcriptome analyses reveal dynamic time-dependent effects of 56Fe, 16O, and 28Si irradiation on the induction of murine hepatocellular carcinoma

Abstract

One of the health risks posed to astronauts during deep space flights is exposure to high charge, high-energy (HZE) ions (Z > 13), which can lead to the induction of hepatocellular carcinoma (HCC). However, little is known on the molecular mechanisms of HZE irradiation-induced HCC. We performed comparative RNA-Seq transcriptomic analyses to assess the carcinogenic effects of 600 MeV/n 56Fe (0.2 Gy), 1 GeV/n 16O (0.2 Gy), and 350 MeV/n 28Si (0.2 Gy) ions in a mouse model for irradiation-induced HCC. C3H/HeNCrl mice were subjected to total body irradiation to simulate space environment HZE-irradiation, and liver tissues were extracted at five different time points post-irradiation to investigate the time-dependent carcinogenic response at the transcriptomic level. Our data demonstrated a clear difference in the biological effects of these HZE ions, particularly immunological, such as Acute Phase Response Signaling, B Cell Receptor Signaling, IL-8 Signaling, and ROS Production in Macrophages. Also seen in this study were novel unannotated transcripts that were significantly affected by HZE. To investigate the biological functions of these novel transcripts, we used a machine learning technique known as self-organizing maps (SOMs) to characterize the transcriptome expression profiles of 60 samples (45 HZE-irradiated, 15 non-irradiated control) from liver tissues.more » A handful of localized modules in the maps emerged as groups of co-regulated and co-expressed transcripts. The functional context of these modules was discovered using overrepresentation analysis. We found that these spots typically contained enriched populations of transcripts related to specific immunological molecular processes (e.g., Acute Phase Response Signaling, B Cell Receptor Signaling, IL-3 Signaling), and RNA Transcription/Expression. A large number of transcripts were found differentially expressed post-HZE irradiation. These results provide valuable information for uncovering the differences in molecular mechanisms underlying HZE specific induced HCC carcinogenesis. Additionally, a handful of novel differentially expressed unannotated transcripts were discovered for each HZE ion. Taken together, these findings may provide a better understanding of biological mechanisms underlying risks for HCC after HZE irradiation and may also have important implications for the discovery of potential countermeasures against and identification of biomarkers for HZE-induced HCC.« less

Authors:
 [1];  [2];  [1];  [3];  [2]; ORCiD logo [4]
+ Show Author Affiliations
  1. Univ. of Texas Medical Branch, Galveston, TX (United States). Biochemistry and Molecular Biology
  2. Univ. of Texas Medical Branch, Galveston, TX (United States). Pharmacology and Toxicology
  3. The Radiation Effects Research Foundation (RERF), Hiroshima (Japan)
  4. Univ. of Texas Medical Branch, Galveston, TX (United States). Biochemistry and Molecular Biology. Pharmacology and Toxicology
Publication Date:
Research Org.:
National Academy of Sciences, Washington, DC (United States)
Sponsoring Org.:
USDOE Office of Environment, Health, Safety and Security (AU)
OSTI Identifier:
1801028
Grant/Contract Number:  
HS0000031
Resource Type:
Accepted Manuscript
Journal Name:
BMC Genomics
Additional Journal Information:
Journal Volume: 21; Journal Issue: 1; Journal ID: ISSN 1471-2164
Publisher:
Springer
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; RNA-Sequencing; self-organizing maps; novel transcripts; carcinogenesis; tumor microenvironment

Citation Formats

Nia, Anna M., Khanipov, Kamil, Barnette, Brooke L., Ullrich, Robert L., Golovko, George, and Emmett, Mark R. Comparative RNA-Seq transcriptome analyses reveal dynamic time-dependent effects of 56Fe, 16O, and 28Si irradiation on the induction of murine hepatocellular carcinoma. United States: N. p., 2020. Web. doi:10.1186/s12864-020-06869-4.
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Nia, Anna M., Khanipov, Kamil, Barnette, Brooke L., Ullrich, Robert L., Golovko, George, & Emmett, Mark R. Comparative RNA-Seq transcriptome analyses reveal dynamic time-dependent effects of 56Fe, 16O, and 28Si irradiation on the induction of murine hepatocellular carcinoma. United States. https://doi.org/10.1186/s12864-020-06869-4
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Nia, Anna M., Khanipov, Kamil, Barnette, Brooke L., Ullrich, Robert L., Golovko, George, and Emmett, Mark R. Wed . "Comparative RNA-Seq transcriptome analyses reveal dynamic time-dependent effects of 56Fe, 16O, and 28Si irradiation on the induction of murine hepatocellular carcinoma". United States. https://doi.org/10.1186/s12864-020-06869-4. https://www.osti.gov/servlets/purl/1801028.
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@article{osti_1801028,
title = {Comparative RNA-Seq transcriptome analyses reveal dynamic time-dependent effects of 56Fe, 16O, and 28Si irradiation on the induction of murine hepatocellular carcinoma},
author = {Nia, Anna M. and Khanipov, Kamil and Barnette, Brooke L. and Ullrich, Robert L. and Golovko, George and Emmett, Mark R.},
abstractNote = {One of the health risks posed to astronauts during deep space flights is exposure to high charge, high-energy (HZE) ions (Z > 13), which can lead to the induction of hepatocellular carcinoma (HCC). However, little is known on the molecular mechanisms of HZE irradiation-induced HCC. We performed comparative RNA-Seq transcriptomic analyses to assess the carcinogenic effects of 600 MeV/n 56Fe (0.2 Gy), 1 GeV/n 16O (0.2 Gy), and 350 MeV/n 28Si (0.2 Gy) ions in a mouse model for irradiation-induced HCC. C3H/HeNCrl mice were subjected to total body irradiation to simulate space environment HZE-irradiation, and liver tissues were extracted at five different time points post-irradiation to investigate the time-dependent carcinogenic response at the transcriptomic level. Our data demonstrated a clear difference in the biological effects of these HZE ions, particularly immunological, such as Acute Phase Response Signaling, B Cell Receptor Signaling, IL-8 Signaling, and ROS Production in Macrophages. Also seen in this study were novel unannotated transcripts that were significantly affected by HZE. To investigate the biological functions of these novel transcripts, we used a machine learning technique known as self-organizing maps (SOMs) to characterize the transcriptome expression profiles of 60 samples (45 HZE-irradiated, 15 non-irradiated control) from liver tissues. A handful of localized modules in the maps emerged as groups of co-regulated and co-expressed transcripts. The functional context of these modules was discovered using overrepresentation analysis. We found that these spots typically contained enriched populations of transcripts related to specific immunological molecular processes (e.g., Acute Phase Response Signaling, B Cell Receptor Signaling, IL-3 Signaling), and RNA Transcription/Expression. A large number of transcripts were found differentially expressed post-HZE irradiation. These results provide valuable information for uncovering the differences in molecular mechanisms underlying HZE specific induced HCC carcinogenesis. Additionally, a handful of novel differentially expressed unannotated transcripts were discovered for each HZE ion. Taken together, these findings may provide a better understanding of biological mechanisms underlying risks for HCC after HZE irradiation and may also have important implications for the discovery of potential countermeasures against and identification of biomarkers for HZE-induced HCC.},
doi = {10.1186/s12864-020-06869-4},
journal = {BMC Genomics},
number = 1,
volume = 21,
place = {United States},
year = {Wed Jul 01 00:00:00 EDT 2020},
month = {Wed Jul 01 00:00:00 EDT 2020}
}
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