Page 149 - 2014 Printable Abstract Book
P. 149
transcriptional repression of repetitive elements. In the second study, we evaluated the effects of
56
exposure to Fe (0.5 Gy) and protons (0.1 Gy) alone or in combination in C57BL/6 male mice 4 weeks after
56
exposure. We show that combined exposure to Fe and protons resulted in distinct and pronounced
epigenetic alterations in comparison with either source of radiation alone. Specifically, we observed a loss
of methylation of the repetitive element LINE1, which correlated with an increase in its expression. This
hypomethylation was also associated with a decrease in the expression of the maintenance DNA
methyltransferase Dnmt1. In conclusion, we show that exposure to high-LET radiation can result in
significant epigenetic alterations detected in the mouse lung short (4 weeks) and long (22 weeks) term
56
after exposure. Furthermore, combined exposure to Fe and protons results in more pronounced
epigenetic effects that can lead to development of genomic instability and cancer. The work was
supported in part by National Aeronautics and Space Administration [NNJ12ZSA001N to JR],
[NNX10AD59G to GN], UAMS Clinical and Translational Science Award [UL1TR000039 and KL2TR000063],
and the Arkansas Biosciences Institute [IK].
(PS2-23) Identification of non-coding miRNAs involved in the development of radio-induced
2
2
1
1
medulloblastoma. Barbara Tanno ; Simona Leonardi ; Paola Giardullo ; Ilaria De Stefano ; Emanuela
1
1
1
1
3
Pasquali ; Simonetta Pazzaglia ; Michael J. Atkinson ; Anna Saran ; and Mariateresa Mancuso,
Laboratory of Radiation Biology and Biomedicine, Agenzia Nazionale per le Nuove Tecnologie, l’Energia e
1
lo Sviluppo Economico Sostenibile (ENEA), Rome, Italy ; Department of Radiation Physics, Guglielmo
2
Marconi University, Rome, Italy ; and Institute of Radiation Biology, Helmholtz Zentrum, München,
Germany
3
MicroRNAs (miRNAs) are a newly discovered class of non-coding and endogenous RNA molecules
that have emerged as key regulators during the development of both normal tissues and tumors.
Moreover, it have been cleared that these molecules have some roles in several cellular processes such
as stress response, apoptosis, cellular differentiation and proliferation, cellular response to ionizing
radiation.
+/-
Ptch1 knockout mice (Ptch1 ), one of the most powerful and widely studied models of medulloblastoma,
represent an important model for the disease and have provided helpful insights into the early stages of
tumor formation, leading also to establish a strong relationship with ionizing radiation exposure. For this
+/-
reason the Ptch1 mouse is a useful model for studies of changes in the transcription profile of non-
coding RNAs that occur during the development of radio-induced medulloblastoma. To test this
hypothesis, we moved from an in vivo to ex vivo model in order to isolate cerebellar granule cell precursors
+/-
(GCPs), the cell-of-origin for medulloblastoma, from Ptch1 and wild type (wt) mouse cerebella at
postnatal day (P) 2/3. After standardization of the cell culture conditions, we carried out irradiation of
mutant and wt GCPs with 0.1 or 1 Gy of x-rays. RNAs from mutant and wt GCPs at P2 were extracted 4
hours after irradiation. Then we performed the “Mouse Brain Cancer miScript miRNA PCR Array”. This
array profiles the expression of 84 miRNAs known to alter their expression during nervous system-related
carcinogenesis. Results indicate a key role of Let-7 family, found downregulated about 6-fold. This miRNAs
family has been found to be deregulated in human medulloblastomas. Most importantly, it is involved in
controlling the DNA damage response (DDR) signaling networks, is regulated upon radiation treatment
+/-
and promotes pluripotency in irradiated Ptch1 GCPs. All together these evidences identify the Let-7
family as the most promising candidate involved in the development of radio-induced medulloblastoma.
147 | P a g e
56
exposure to Fe (0.5 Gy) and protons (0.1 Gy) alone or in combination in C57BL/6 male mice 4 weeks after
56
exposure. We show that combined exposure to Fe and protons resulted in distinct and pronounced
epigenetic alterations in comparison with either source of radiation alone. Specifically, we observed a loss
of methylation of the repetitive element LINE1, which correlated with an increase in its expression. This
hypomethylation was also associated with a decrease in the expression of the maintenance DNA
methyltransferase Dnmt1. In conclusion, we show that exposure to high-LET radiation can result in
significant epigenetic alterations detected in the mouse lung short (4 weeks) and long (22 weeks) term
56
after exposure. Furthermore, combined exposure to Fe and protons results in more pronounced
epigenetic effects that can lead to development of genomic instability and cancer. The work was
supported in part by National Aeronautics and Space Administration [NNJ12ZSA001N to JR],
[NNX10AD59G to GN], UAMS Clinical and Translational Science Award [UL1TR000039 and KL2TR000063],
and the Arkansas Biosciences Institute [IK].
(PS2-23) Identification of non-coding miRNAs involved in the development of radio-induced
2
2
1
1
medulloblastoma. Barbara Tanno ; Simona Leonardi ; Paola Giardullo ; Ilaria De Stefano ; Emanuela
1
1
1
1
3
Pasquali ; Simonetta Pazzaglia ; Michael J. Atkinson ; Anna Saran ; and Mariateresa Mancuso,
Laboratory of Radiation Biology and Biomedicine, Agenzia Nazionale per le Nuove Tecnologie, l’Energia e
1
lo Sviluppo Economico Sostenibile (ENEA), Rome, Italy ; Department of Radiation Physics, Guglielmo
2
Marconi University, Rome, Italy ; and Institute of Radiation Biology, Helmholtz Zentrum, München,
Germany
3
MicroRNAs (miRNAs) are a newly discovered class of non-coding and endogenous RNA molecules
that have emerged as key regulators during the development of both normal tissues and tumors.
Moreover, it have been cleared that these molecules have some roles in several cellular processes such
as stress response, apoptosis, cellular differentiation and proliferation, cellular response to ionizing
radiation.
+/-
Ptch1 knockout mice (Ptch1 ), one of the most powerful and widely studied models of medulloblastoma,
represent an important model for the disease and have provided helpful insights into the early stages of
tumor formation, leading also to establish a strong relationship with ionizing radiation exposure. For this
+/-
reason the Ptch1 mouse is a useful model for studies of changes in the transcription profile of non-
coding RNAs that occur during the development of radio-induced medulloblastoma. To test this
hypothesis, we moved from an in vivo to ex vivo model in order to isolate cerebellar granule cell precursors
+/-
(GCPs), the cell-of-origin for medulloblastoma, from Ptch1 and wild type (wt) mouse cerebella at
postnatal day (P) 2/3. After standardization of the cell culture conditions, we carried out irradiation of
mutant and wt GCPs with 0.1 or 1 Gy of x-rays. RNAs from mutant and wt GCPs at P2 were extracted 4
hours after irradiation. Then we performed the “Mouse Brain Cancer miScript miRNA PCR Array”. This
array profiles the expression of 84 miRNAs known to alter their expression during nervous system-related
carcinogenesis. Results indicate a key role of Let-7 family, found downregulated about 6-fold. This miRNAs
family has been found to be deregulated in human medulloblastomas. Most importantly, it is involved in
controlling the DNA damage response (DDR) signaling networks, is regulated upon radiation treatment
+/-
and promotes pluripotency in irradiated Ptch1 GCPs. All together these evidences identify the Let-7
family as the most promising candidate involved in the development of radio-induced medulloblastoma.
147 | P a g e
