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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.


HZE particle radiation-associated increases in micro-nucleated cells.(A) Representative microphotographs showing micro-nucleated cells in the brain, kidney, liver, lung, and spleen tissues from mice exposed to HZE particle radiation. Arrowheads point to the micronucleus in each region. (B) Histograms obtained from the double-blinded quantification of micro-nucleated cells from brain, kidney, liver, lung, and spleen tissues from mock-IR and HZE particle radiation-exposed mice, showing an HZE-associated significant increase in micronuclei in brain, kidney, and lung tissues.
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f7: HZE particle radiation-associated increases in micro-nucleated cells.(A) Representative microphotographs showing micro-nucleated cells in the brain, kidney, liver, lung, and spleen tissues from mice exposed to HZE particle radiation. Arrowheads point to the micronucleus in each region. (B) Histograms obtained from the double-blinded quantification of micro-nucleated cells from brain, kidney, liver, lung, and spleen tissues from mock-IR and HZE particle radiation-exposed mice, showing an HZE-associated significant increase in micronuclei in brain, kidney, and lung tissues.

Mentions: Micronuclei are widely used as the biomarker for elevated risk in mammalian cells, cultured/exfoliated cells, and biopsy samples46. Micronuclei are a reflection of clastogenic events and indicate the ongoing process of DNA damage. This biomarker been correlated with cancer risk at several sites, and its use has been shown to be economical. In addition, micronuclei assay has been used as a biological dosimeter of in vivo ionizing radiation exposure474849. In the current study, the frequency of micro-nucleated cells was uniformly elevated in all tissues (brain, liver, kidney, lung, and spleen) from the mice exposed to HZE particle radiation (Fig. 7A and B). Double-blinded scoring of micronuclei quantification revealed a significant increase in micronuclei in brain (P < 0.001), kidney (P < 0.001), and lung (P < 0.01) tissues (Fig. 7B). An increased number of micro-nucleated cells suggest a strong biological effect on chromosomes and chromatid fragments, which responded dramatically to high-LET radiation.


High Energy Particle Radiation-associated Oncogenic Transformation in Normal Mice: Insight into the Connection between Activation of Oncotargets and Oncogene Addiction
HZE particle radiation-associated increases in micro-nucleated cells.(A) Representative microphotographs showing micro-nucleated cells in the brain, kidney, liver, lung, and spleen tissues from mice exposed to HZE particle radiation. Arrowheads point to the micronucleus in each region. (B) Histograms obtained from the double-blinded quantification of micro-nucleated cells from brain, kidney, liver, lung, and spleen tissues from mock-IR and HZE particle radiation-exposed mice, showing an HZE-associated significant increase in micronuclei in brain, kidney, and lung tissues.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f7: HZE particle radiation-associated increases in micro-nucleated cells.(A) Representative microphotographs showing micro-nucleated cells in the brain, kidney, liver, lung, and spleen tissues from mice exposed to HZE particle radiation. Arrowheads point to the micronucleus in each region. (B) Histograms obtained from the double-blinded quantification of micro-nucleated cells from brain, kidney, liver, lung, and spleen tissues from mock-IR and HZE particle radiation-exposed mice, showing an HZE-associated significant increase in micronuclei in brain, kidney, and lung tissues.
Mentions: Micronuclei are widely used as the biomarker for elevated risk in mammalian cells, cultured/exfoliated cells, and biopsy samples46. Micronuclei are a reflection of clastogenic events and indicate the ongoing process of DNA damage. This biomarker been correlated with cancer risk at several sites, and its use has been shown to be economical. In addition, micronuclei assay has been used as a biological dosimeter of in vivo ionizing radiation exposure474849. In the current study, the frequency of micro-nucleated cells was uniformly elevated in all tissues (brain, liver, kidney, lung, and spleen) from the mice exposed to HZE particle radiation (Fig. 7A and B). Double-blinded scoring of micronuclei quantification revealed a significant increase in micronuclei in brain (P < 0.001), kidney (P < 0.001), and lung (P < 0.01) tissues (Fig. 7B). An increased number of micro-nucleated cells suggest a strong biological effect on chromosomes and chromatid fragments, which responded dramatically to high-LET radiation.

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&thinsp;MeV/amu; 0.5&thinsp;Gy/min; 0.8&thinsp;Gy) particle radiation and compared the response with low LET &gamma;-radiation (137Cs; 0.5&thinsp;Gy/min; 2&thinsp;Gy). One of the novel findings is the &lsquo;tissue-independent&rsquo; 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.