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High Energy Particle Radiation-associated Oncogenic Transformation in Normal Mice: Insight into the Connection between Activation of Oncotargets and Oncogene Addiction

View Article: PubMed Central - PubMed

ABSTRACT

Concerns on high-energy particle radiation-induced tumorigenic transformation of normal tissue in astronauts, and in cancer patients undergoing radiotherapy, emphasizes the significance of elucidating the mechanisms involved in radiogenic transformation processes. Mostly used genetically modified or tumor-prone models are less reliable in determining human health risk in space or protracted post-treatment normal tissue toxicity. Here, in wild type C57BL/6 mice, we related the deregulation of distinctive set of tissue-specific oncotargets in major organs upon 56Fe (600 MeV/amu; 0.5 Gy/min; 0.8 Gy) particle radiation and compared the response with low LET γ-radiation (137Cs; 0.5 Gy/min; 2 Gy). One of the novel findings is the ‘tissue-independent’ activation of TAL2 upon high-energy radiation, and thus qualifies TAL2 as a potential biomarker for particle and other qualities of radiation. Heightened expression of TAL2 gene transcript, which sustained over four weeks post-irradiation foster the concept of oncogene addiction signaling in radiogenic transformation. The positive/negative expression of other selected oncotargets that expresses tissue-dependent manner indicated their role as a secondary driving force that addresses the diversity of tissue-dependent characteristics of tumorigenesis. This study, while reporting novel findings on radiogenic transformation of normal tissue when exposed to particle radiation, it also provides a platform for further investigation into different radiation quality, LET and dose/dose rate effect in healthy organs.

No MeSH data available.


Related in: MedlinePlus

(A) Heat map showing the transcriptional expression status of each oncogene across the tissues investigated after HZE particle radiation or low-LET radiation, arranged in alphabetical order. The tissue scoring and expression of each oncogene in numerous tissues were also included. HZE particle radiation resulted in the heightened transcription of TAL2 in seven of the 8 tissues investigated. Green: activated transcription; Yellow: non-activated or decreased transcription. (B) Venn diagrams constructed from High-LET: low-LET radiation crisscross analysis of activation sustained oncogenes in brain, gut, kidney, large intestine (LI), liver, lungs, small intestine (SI) and spleen showing exclusive HZE ion exposure response. Numbers in small circles outside the Venn diagram = total number of oncogenes activated in response to high/Low-LET radiation; numbers in bigger circles = genes activated exclusively in response to high/low-LET radiation; numbers in overlapping region = genes activated in common between high- and low-LET radiation.
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f2: (A) Heat map showing the transcriptional expression status of each oncogene across the tissues investigated after HZE particle radiation or low-LET radiation, arranged in alphabetical order. The tissue scoring and expression of each oncogene in numerous tissues were also included. HZE particle radiation resulted in the heightened transcription of TAL2 in seven of the 8 tissues investigated. Green: activated transcription; Yellow: non-activated or decreased transcription. (B) Venn diagrams constructed from High-LET: low-LET radiation crisscross analysis of activation sustained oncogenes in brain, gut, kidney, large intestine (LI), liver, lungs, small intestine (SI) and spleen showing exclusive HZE ion exposure response. Numbers in small circles outside the Venn diagram = total number of oncogenes activated in response to high/Low-LET radiation; numbers in bigger circles = genes activated exclusively in response to high/low-LET radiation; numbers in overlapping region = genes activated in common between high- and low-LET radiation.

Mentions: Tissue comparison analysis after particle radiation exposure revealed no tissue-independent transcriptional activation of any oncogene either after HZE ion or low-LET radiation (Fig. 2A). However, Tal2 showed near tissue-independent activation with increased levels in all tissues investigated, except mouse gut tissues with HZE ion. In addition, three genes, Msh2, Pim1, and Tfdp2, were increased at least in six of the eight tissue types investigated (Fig. 2A). A number of genes showed tissue-independent expression patterns, with 11 genes that were activated across at least 5 tissues, 21 genes activated across at least 4 tissues, 20 genes activated across at least 3 tissues, and 23 genes activated across at least 2 tissues after high-LET radiation exposure. Conversely, 8 genes showed tissue-dependent expression, with ABL2 and VAV only in the small intestine and AKAP13, AKT2, BCL2, ELK1, LCK, and NTRK1 only in liver tissues (Fig. 2A). Interestingly, one gene, ABL1, remained unaltered in all tissues after high-LET radiation exposure. In disparity, AKT2 and STAT3 showed near tissue-independent activation (at least in six tissues) with low-LET radiation. In addition, 7 genes, Abl1, Lyn, Nras, Ros1, Tal2, Tlx1 and Vav were increased at least in five of the eight tissue types investigated (Fig. 2A). Also many genes showed tissue-independent expression patterns, with 14 genes that were activated across at least 4 tissues, 16 genes activated across at least 3 tissues, and 17 genes activated across at least 2 tissues, after low-LET radiation exposure (Fig. 2A). Conversely, 15 genes showed tissue-dependent expression and 17 genes remained unaltered in all tissues after low-LET radiation exposure (Fig. 2A).


High Energy Particle Radiation-associated Oncogenic Transformation in Normal Mice: Insight into the Connection between Activation of Oncotargets and Oncogene Addiction
(A) Heat map showing the transcriptional expression status of each oncogene across the tissues investigated after HZE particle radiation or low-LET radiation, arranged in alphabetical order. The tissue scoring and expression of each oncogene in numerous tissues were also included. HZE particle radiation resulted in the heightened transcription of TAL2 in seven of the 8 tissues investigated. Green: activated transcription; Yellow: non-activated or decreased transcription. (B) Venn diagrams constructed from High-LET: low-LET radiation crisscross analysis of activation sustained oncogenes in brain, gut, kidney, large intestine (LI), liver, lungs, small intestine (SI) and spleen showing exclusive HZE ion exposure response. Numbers in small circles outside the Venn diagram = total number of oncogenes activated in response to high/Low-LET radiation; numbers in bigger circles = genes activated exclusively in response to high/low-LET radiation; numbers in overlapping region = genes activated in common between high- and low-LET radiation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5120307&req=5

f2: (A) Heat map showing the transcriptional expression status of each oncogene across the tissues investigated after HZE particle radiation or low-LET radiation, arranged in alphabetical order. The tissue scoring and expression of each oncogene in numerous tissues were also included. HZE particle radiation resulted in the heightened transcription of TAL2 in seven of the 8 tissues investigated. Green: activated transcription; Yellow: non-activated or decreased transcription. (B) Venn diagrams constructed from High-LET: low-LET radiation crisscross analysis of activation sustained oncogenes in brain, gut, kidney, large intestine (LI), liver, lungs, small intestine (SI) and spleen showing exclusive HZE ion exposure response. Numbers in small circles outside the Venn diagram = total number of oncogenes activated in response to high/Low-LET radiation; numbers in bigger circles = genes activated exclusively in response to high/low-LET radiation; numbers in overlapping region = genes activated in common between high- and low-LET radiation.
Mentions: Tissue comparison analysis after particle radiation exposure revealed no tissue-independent transcriptional activation of any oncogene either after HZE ion or low-LET radiation (Fig. 2A). However, Tal2 showed near tissue-independent activation with increased levels in all tissues investigated, except mouse gut tissues with HZE ion. In addition, three genes, Msh2, Pim1, and Tfdp2, were increased at least in six of the eight tissue types investigated (Fig. 2A). A number of genes showed tissue-independent expression patterns, with 11 genes that were activated across at least 5 tissues, 21 genes activated across at least 4 tissues, 20 genes activated across at least 3 tissues, and 23 genes activated across at least 2 tissues after high-LET radiation exposure. Conversely, 8 genes showed tissue-dependent expression, with ABL2 and VAV only in the small intestine and AKAP13, AKT2, BCL2, ELK1, LCK, and NTRK1 only in liver tissues (Fig. 2A). Interestingly, one gene, ABL1, remained unaltered in all tissues after high-LET radiation exposure. In disparity, AKT2 and STAT3 showed near tissue-independent activation (at least in six tissues) with low-LET radiation. In addition, 7 genes, Abl1, Lyn, Nras, Ros1, Tal2, Tlx1 and Vav were increased at least in five of the eight tissue types investigated (Fig. 2A). Also many genes showed tissue-independent expression patterns, with 14 genes that were activated across at least 4 tissues, 16 genes activated across at least 3 tissues, and 17 genes activated across at least 2 tissues, after low-LET radiation exposure (Fig. 2A). Conversely, 15 genes showed tissue-dependent expression and 17 genes remained unaltered in all tissues after low-LET radiation exposure (Fig. 2A).

View Article: PubMed Central - PubMed

ABSTRACT

Concerns on high-energy particle radiation-induced tumorigenic transformation of normal tissue in astronauts, and in cancer patients undergoing radiotherapy, emphasizes the significance of elucidating the mechanisms involved in radiogenic transformation processes. Mostly used genetically modified or tumor-prone models are less reliable in determining human health risk in space or protracted post-treatment normal tissue toxicity. Here, in wild type C57BL/6 mice, we related the deregulation of distinctive set of tissue-specific oncotargets in major organs upon 56Fe (600 MeV/amu; 0.5 Gy/min; 0.8 Gy) particle radiation and compared the response with low LET γ-radiation (137Cs; 0.5 Gy/min; 2 Gy). One of the novel findings is the ‘tissue-independent’ activation of TAL2 upon high-energy radiation, and thus qualifies TAL2 as a potential biomarker for particle and other qualities of radiation. Heightened expression of TAL2 gene transcript, which sustained over four weeks post-irradiation foster the concept of oncogene addiction signaling in radiogenic transformation. The positive/negative expression of other selected oncotargets that expresses tissue-dependent manner indicated their role as a secondary driving force that addresses the diversity of tissue-dependent characteristics of tumorigenesis. This study, while reporting novel findings on radiogenic transformation of normal tissue when exposed to particle radiation, it also provides a platform for further investigation into different radiation quality, LET and dose/dose rate effect in healthy organs.

No MeSH data available.


Related in: MedlinePlus