Page 158 - 2014 Printable Abstract Book
P. 158
(PS2-39) Mitochondrial DNA content alterations in HZE radiation-induced liver carcinogenesis. Yongjia
2
1
1
1
1
1
Yu ; Maureen A. McCarthy ; Astrid D. Corbitt ; Lauren Macias ; Daniel Olivares ; F. Andrew Ray ; Michael
2
1
1
M. Weil ; and Robert L. Ullrich, University of Texas Medical Branch, Galveston, TX and Colorado State
2
University, Fort Collins, CO
56
28
We previously reported that C3H mice exposed to Fe- and Si- particle irradiations had a
significantly higher incidence of hepatocellular carcinomas (HCC) in comparison to gamma-irradiated
mice. Using real-time quantitative PCR, we examined mitochondrial DNA content in paired HCC tumor
56
and normal margin samples from Fe-irradiated mice. Mitochondrial DNA depletion was detected in
these tumors, similar to reported cases in human HCC patients. This decrease of mitochondrial DNA
content may reflect the Warburg effect in that certain types of tumor cells rely on glycolysis more than
oxidative phosphorylation (OXPHOS) for cellular energy metabolism to gain competitive growth
advantages. To further investigate the potential role of mitochondrial DNA in the initiation and
56
progression of HZE-induced HCC, we have analyzed liver samples of Fe-irradiated C3H mice and age-
matched non-irradiated controls collected at different time points. At one month post-irradiation, the
56
mitochondrial DNA content in the Fe-treated mouse livers actually increased by an average of more than
40% over control. This correlates with the observed increased oxidative stress in the liver. However, at
the six-month time point, the mitochondrial DNA content in the irradiated group dropped substantially,
i.e. to about 75% of that in the controls. In our studies most HCCs were detected at least one year post
irradiation and none were found at the six month time-point. These observations suggest that the
mitochondrial DNA content alterations may contribute to the HZE-induced liver carcinogenesis. (This
study is funded by NASA NSCOR grant NNX12AB54G)
1;2
(PS2-40) Mechanisms of mouse T-cell lymphomagenesis after infant irradiation. Masaaki Sunaoshi ;
2
2
2
2
2
Yoshiko Amasaki ; Shinobu Hirano-Sakairi ; Benjamin J. Blyth ; Kazuhiro Daino ; Yi Shang ; Chizuru
2
2
1
2
2
Tsuruoka ; Takamitsu Morioka ; Mayumi Nishimura ; Yoshiya Shimada ; Akira Tachibana ; and Shizuko
2
1
Kakinuma, College of Science, Ibaraki University, 2-1-1 Bunkyo, Mito, Japan and Radiobiology for
Children’s Health Program, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba,
2
Japan
Studies of survivors after A-bombing and Chernobyl accident show that radiation carcinogenesis
is dependent on age at exposure. For instance, the risk of leukemia and thyroid cancer is quite high after
childhood exposure compared to adulthood exposure. Given that the medical use of radiation, such as
CT, is recently increasing, it is important to understand the risks and mechanism of radiation
carcinogenesis after childhood exposure. We previously analyzed genetic changes in mouse T-cell
lymphomas (TL) induced by weekly exposure to 1.2 Gy X-rays for 4 weeks, starting at 1 week (infant), 4
weeks (prepuberty) or 8 weeks (young adult) of age. We observed that Pten was frequently mutated in
TL, coupled with recombination-mediated loss of heterozygosity (LOH), after infant irradiation compared
to young adult irradiation (P = 0.041). On the other hand, Ikaros mutations, which were coupled with
deletion-mediated LOH, were more frequently observed in TL arising after young adult irradiation (P =
0.22). Why are the impaired tumor-suppressor pathways different in TL induced by radiation at different
ages? We hypothesize here that cell cycle (G1) checkpoint and DNA repair pathways (homologous
recombination vs. non-homologous end joining) differ between infant and adult thymocytes. To
investigate these possibilities, we irradiate B6C3F1 mice at either 1 or 8 weeks of age and isolate CD4/CD8
156 | P a g e
2
1
1
1
1
1
Yu ; Maureen A. McCarthy ; Astrid D. Corbitt ; Lauren Macias ; Daniel Olivares ; F. Andrew Ray ; Michael
2
1
1
M. Weil ; and Robert L. Ullrich, University of Texas Medical Branch, Galveston, TX and Colorado State
2
University, Fort Collins, CO
56
28
We previously reported that C3H mice exposed to Fe- and Si- particle irradiations had a
significantly higher incidence of hepatocellular carcinomas (HCC) in comparison to gamma-irradiated
mice. Using real-time quantitative PCR, we examined mitochondrial DNA content in paired HCC tumor
56
and normal margin samples from Fe-irradiated mice. Mitochondrial DNA depletion was detected in
these tumors, similar to reported cases in human HCC patients. This decrease of mitochondrial DNA
content may reflect the Warburg effect in that certain types of tumor cells rely on glycolysis more than
oxidative phosphorylation (OXPHOS) for cellular energy metabolism to gain competitive growth
advantages. To further investigate the potential role of mitochondrial DNA in the initiation and
56
progression of HZE-induced HCC, we have analyzed liver samples of Fe-irradiated C3H mice and age-
matched non-irradiated controls collected at different time points. At one month post-irradiation, the
56
mitochondrial DNA content in the Fe-treated mouse livers actually increased by an average of more than
40% over control. This correlates with the observed increased oxidative stress in the liver. However, at
the six-month time point, the mitochondrial DNA content in the irradiated group dropped substantially,
i.e. to about 75% of that in the controls. In our studies most HCCs were detected at least one year post
irradiation and none were found at the six month time-point. These observations suggest that the
mitochondrial DNA content alterations may contribute to the HZE-induced liver carcinogenesis. (This
study is funded by NASA NSCOR grant NNX12AB54G)
1;2
(PS2-40) Mechanisms of mouse T-cell lymphomagenesis after infant irradiation. Masaaki Sunaoshi ;
2
2
2
2
2
Yoshiko Amasaki ; Shinobu Hirano-Sakairi ; Benjamin J. Blyth ; Kazuhiro Daino ; Yi Shang ; Chizuru
2
2
1
2
2
Tsuruoka ; Takamitsu Morioka ; Mayumi Nishimura ; Yoshiya Shimada ; Akira Tachibana ; and Shizuko
2
1
Kakinuma, College of Science, Ibaraki University, 2-1-1 Bunkyo, Mito, Japan and Radiobiology for
Children’s Health Program, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba,
2
Japan
Studies of survivors after A-bombing and Chernobyl accident show that radiation carcinogenesis
is dependent on age at exposure. For instance, the risk of leukemia and thyroid cancer is quite high after
childhood exposure compared to adulthood exposure. Given that the medical use of radiation, such as
CT, is recently increasing, it is important to understand the risks and mechanism of radiation
carcinogenesis after childhood exposure. We previously analyzed genetic changes in mouse T-cell
lymphomas (TL) induced by weekly exposure to 1.2 Gy X-rays for 4 weeks, starting at 1 week (infant), 4
weeks (prepuberty) or 8 weeks (young adult) of age. We observed that Pten was frequently mutated in
TL, coupled with recombination-mediated loss of heterozygosity (LOH), after infant irradiation compared
to young adult irradiation (P = 0.041). On the other hand, Ikaros mutations, which were coupled with
deletion-mediated LOH, were more frequently observed in TL arising after young adult irradiation (P =
0.22). Why are the impaired tumor-suppressor pathways different in TL induced by radiation at different
ages? We hypothesize here that cell cycle (G1) checkpoint and DNA repair pathways (homologous
recombination vs. non-homologous end joining) differ between infant and adult thymocytes. To
investigate these possibilities, we irradiate B6C3F1 mice at either 1 or 8 weeks of age and isolate CD4/CD8
156 | P a g e
