Limits...
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

Histograms obtained from the quantitative QPCR profiling showing transcriptional modifications of 88 oncogenes in mouse brain, gut, kidney, liver, lung, spleen, and large and small intestine in response to HZE 56Fe particle radiation exposure.A custom-made transcriptome profiler with an archive of a unique oncogene profile pertaining to interacting functional networks of oncogene addiction that govern cellular signaling and drive the initiation of carcinogenic processes was used. Individual gene expression levels were background subtracted. The inter-profile variations are normalized with internal positive/housekeeping controls. The relative expression level of each gene is expressed as fold change compared with the mock-IR controls (mean and SD). Group-wise comparisons were made using GraphPad PRISM. For ease of comparison, all genes investigated, irrespective of their expression status, are included in the graph.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC5120307&req=5

f1: Histograms obtained from the quantitative QPCR profiling showing transcriptional modifications of 88 oncogenes in mouse brain, gut, kidney, liver, lung, spleen, and large and small intestine in response to HZE 56Fe particle radiation exposure.A custom-made transcriptome profiler with an archive of a unique oncogene profile pertaining to interacting functional networks of oncogene addiction that govern cellular signaling and drive the initiation of carcinogenic processes was used. Individual gene expression levels were background subtracted. The inter-profile variations are normalized with internal positive/housekeeping controls. The relative expression level of each gene is expressed as fold change compared with the mock-IR controls (mean and SD). Group-wise comparisons were made using GraphPad PRISM. For ease of comparison, all genes investigated, irrespective of their expression status, are included in the graph.

Mentions: To define the high-energy particle radiation-associated oncogenic addiction in healthy tissues, we examined the oncogenic biomarker transcription profile after iron ion exposure (600 MeV/u; 0.8 Gy at 0.5 Gy/min) in major organ sites, including the brain, gut, kidney, large intestine, small intestine, liver, lung, and spleen. We used a mouse oncogene quantitative PCR profile (Realtimeprimers.com, Elkins Park, PA) that comprises the customized archive of 88 oncotargets and is equipped with eight internal positive and negative controls (Table S1). Exposing the animals to whole body high-LET radiation prompted a wide range of oncogene transcriptional responses in every tissue investigated. Compared with mock-irradiated controls, HZE ion radiation specifically activated transcription of 19 oncogenes, including Axl, Brca1, Gtf2h1, Jund, Lmo1, Lmo2, Lyl1, Mas1, Mdm2, Mos, Msh2, Myb, Myc, Mycn, Nfkb2, Nras, Pim1, Pms2, and Tal2 in the mouse brain (Fig. 1). Likewise, high-LET radiation resulted in the activation of 30 oncogenes (Egfr, Fes, Fgf4, Fgfr2, Fosb, Fosl2, Hgf, Hras1, Junb, Junc, Kit, Kras, Mcf2, Mdm2, Msh2, Mycl1, Nfkb2, Nras, Nrg1, Pdgfa, Pms2, Rb1, Ski, Tfdp2, Tgfb1, Tgfb2, Tiam1, Tlx1, Tsc2, Vegfa) in the mouse gut (Fig. 1). Further, HZE ion radiation induced 37 genes (Axl, Bcl3, Brca2, Egfr, Erbb2, Fes, Fosb, Gip, Gli1, Gtf2h1, Hgf, Junc, Kras, Lyn, Mdm2, Mlh1, Mos, Msh2, Myb, Mycn, Nfkb1, Nras, Nrg1, Pdgfb, Pim1, Pms1, Pms2, Raf1, Ros1, Stat3, Tal1, Tal2, Tcfl2, Tfdp2, Tgfb1, Tgfb2, Tiam1) in kidney tissues (Fig. 1). In addition, we found transcriptional activation of 21 genes (Bcl3, Msh2, Myb, Mycn, Pdgfa, Pdgfb, Pim1, Pms2, Raf1, Rb1, Ski, Src, Stat3, Stat5b, Tal1, Tal2, Tcfl2, Tfdp2, Tgfb1, Tgfb2, Tsc2) in the large intestine and another 63 oncogenes (Abl2, Alk, Axl, Bcl3, Bcl6, Brca2, ccnd1, Csf1r, E2f1, E2f3, Egfr, Erbb2, Erbb4, Fes, Fgf4, Fgfr2, Fgr, Fos, Fosb, Fosl1, Fosl2, Foxo1, Gip, Gli1, Gtf2h1, Hras1, Junb, Junc, Jund, Kit, Kras, Lmo2, Lyl1, Mas1, Mcf2, Mcf2l, Mdm2, Met, Mlh1, Mll1, Msh2, Nfkb1, Nfkb2, Nrg1, Pax5, Pdgfa, Pdgfb, Pim1, Raf1, Rb1, Ret, Runx1, Ski, Src, Stat5b, Tal1, Tal2, Tfdp2, Tgfb1, Tiam1, Tlx1, Vav, Vegfa) in the small intestine tissues of mice exposed to iron ions (Fig. 1). Moreover, high-LET radiation led to the transcriptional activation of 8 (Mos, Ski, Stat3, Tal1, Tal2, Tcfl2, Tfdp2, Tgfb2) oncogenes in the spleen and another 23 oncogenes (Csf1r, E2f1, Erbb3, Fes, Fgr, Fos, Fosb, Gip, Gli1, Gtf2h1, Jund, Lmo2, Lyl1, Lyn, Met, Mlh1, Mos, Myc, Mycn, Nfkb1, Pim1, Rb1, Tal2) in lung tissues (Fig. 1). We observed a magnified oncogenic transcription response in liver tissues, with increased expression of 78 oncogenes after high-LET radiation (Fig. 1).


High Energy Particle Radiation-associated Oncogenic Transformation in Normal Mice: Insight into the Connection between Activation of Oncotargets and Oncogene Addiction
Histograms obtained from the quantitative QPCR profiling showing transcriptional modifications of 88 oncogenes in mouse brain, gut, kidney, liver, lung, spleen, and large and small intestine in response to HZE 56Fe particle radiation exposure.A custom-made transcriptome profiler with an archive of a unique oncogene profile pertaining to interacting functional networks of oncogene addiction that govern cellular signaling and drive the initiation of carcinogenic processes was used. Individual gene expression levels were background subtracted. The inter-profile variations are normalized with internal positive/housekeeping controls. The relative expression level of each gene is expressed as fold change compared with the mock-IR controls (mean and SD). Group-wise comparisons were made using GraphPad PRISM. For ease of comparison, all genes investigated, irrespective of their expression status, are included in the graph.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f1: Histograms obtained from the quantitative QPCR profiling showing transcriptional modifications of 88 oncogenes in mouse brain, gut, kidney, liver, lung, spleen, and large and small intestine in response to HZE 56Fe particle radiation exposure.A custom-made transcriptome profiler with an archive of a unique oncogene profile pertaining to interacting functional networks of oncogene addiction that govern cellular signaling and drive the initiation of carcinogenic processes was used. Individual gene expression levels were background subtracted. The inter-profile variations are normalized with internal positive/housekeeping controls. The relative expression level of each gene is expressed as fold change compared with the mock-IR controls (mean and SD). Group-wise comparisons were made using GraphPad PRISM. For ease of comparison, all genes investigated, irrespective of their expression status, are included in the graph.
Mentions: To define the high-energy particle radiation-associated oncogenic addiction in healthy tissues, we examined the oncogenic biomarker transcription profile after iron ion exposure (600 MeV/u; 0.8 Gy at 0.5 Gy/min) in major organ sites, including the brain, gut, kidney, large intestine, small intestine, liver, lung, and spleen. We used a mouse oncogene quantitative PCR profile (Realtimeprimers.com, Elkins Park, PA) that comprises the customized archive of 88 oncotargets and is equipped with eight internal positive and negative controls (Table S1). Exposing the animals to whole body high-LET radiation prompted a wide range of oncogene transcriptional responses in every tissue investigated. Compared with mock-irradiated controls, HZE ion radiation specifically activated transcription of 19 oncogenes, including Axl, Brca1, Gtf2h1, Jund, Lmo1, Lmo2, Lyl1, Mas1, Mdm2, Mos, Msh2, Myb, Myc, Mycn, Nfkb2, Nras, Pim1, Pms2, and Tal2 in the mouse brain (Fig. 1). Likewise, high-LET radiation resulted in the activation of 30 oncogenes (Egfr, Fes, Fgf4, Fgfr2, Fosb, Fosl2, Hgf, Hras1, Junb, Junc, Kit, Kras, Mcf2, Mdm2, Msh2, Mycl1, Nfkb2, Nras, Nrg1, Pdgfa, Pms2, Rb1, Ski, Tfdp2, Tgfb1, Tgfb2, Tiam1, Tlx1, Tsc2, Vegfa) in the mouse gut (Fig. 1). Further, HZE ion radiation induced 37 genes (Axl, Bcl3, Brca2, Egfr, Erbb2, Fes, Fosb, Gip, Gli1, Gtf2h1, Hgf, Junc, Kras, Lyn, Mdm2, Mlh1, Mos, Msh2, Myb, Mycn, Nfkb1, Nras, Nrg1, Pdgfb, Pim1, Pms1, Pms2, Raf1, Ros1, Stat3, Tal1, Tal2, Tcfl2, Tfdp2, Tgfb1, Tgfb2, Tiam1) in kidney tissues (Fig. 1). In addition, we found transcriptional activation of 21 genes (Bcl3, Msh2, Myb, Mycn, Pdgfa, Pdgfb, Pim1, Pms2, Raf1, Rb1, Ski, Src, Stat3, Stat5b, Tal1, Tal2, Tcfl2, Tfdp2, Tgfb1, Tgfb2, Tsc2) in the large intestine and another 63 oncogenes (Abl2, Alk, Axl, Bcl3, Bcl6, Brca2, ccnd1, Csf1r, E2f1, E2f3, Egfr, Erbb2, Erbb4, Fes, Fgf4, Fgfr2, Fgr, Fos, Fosb, Fosl1, Fosl2, Foxo1, Gip, Gli1, Gtf2h1, Hras1, Junb, Junc, Jund, Kit, Kras, Lmo2, Lyl1, Mas1, Mcf2, Mcf2l, Mdm2, Met, Mlh1, Mll1, Msh2, Nfkb1, Nfkb2, Nrg1, Pax5, Pdgfa, Pdgfb, Pim1, Raf1, Rb1, Ret, Runx1, Ski, Src, Stat5b, Tal1, Tal2, Tfdp2, Tgfb1, Tiam1, Tlx1, Vav, Vegfa) in the small intestine tissues of mice exposed to iron ions (Fig. 1). Moreover, high-LET radiation led to the transcriptional activation of 8 (Mos, Ski, Stat3, Tal1, Tal2, Tcfl2, Tfdp2, Tgfb2) oncogenes in the spleen and another 23 oncogenes (Csf1r, E2f1, Erbb3, Fes, Fgr, Fos, Fosb, Gip, Gli1, Gtf2h1, Jund, Lmo2, Lyl1, Lyn, Met, Mlh1, Mos, Myc, Mycn, Nfkb1, Pim1, Rb1, Tal2) in lung tissues (Fig. 1). We observed a magnified oncogenic transcription response in liver tissues, with increased expression of 78 oncogenes after high-LET radiation (Fig. 1).

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