Page 142 - 2014 Printable Abstract Book
P. 142
The states of all species, the relationships among all signaling proteins, metabolic flux distribution, and
the thermodynamic and stoichiometric characteristics of metabolites were jointly optimized using a
constraint-based approach and mixed integer programming. We will present the data that was used in
the development of the network model and data that support the predictions of the model in relation to
the response to radiation or Erlotinib treatment. These include data demonstrating a mechanistic
connection between increased reactive oxygen species (ROS), cellular bioenergetics, lipid metabolism and
response to radiation and Erlotinib treatment. Understanding the underlying mechanisms associated with
response to radiation and drug targeted therapies will provide new insight to how HNSCC cells acquire
resistance to current therapy treatments and new clinical targets for treatment of radiation-resistant
HNSCC.
(PS2-08) Transcriptome and miRNA profiling of radiation-induced murine HCC in tissues and plasma.
2
1
2
4
3
Lianghao Ding ; Yongjia Yu, PhD ; Robert L. Ullrich ; Michael M. Weil ; Andrew Ray ; and Michael D. Story, 1
1
The University of Texas Southwestern Medical Center, Dallas, TX ; The University of Texas Medical Branch,
4
2
3
Galveston, TX ; Colorado State University, Fort Collins, CO ; and Colorado State University, Fot Colins, CO
HZE particle (56Fe and 28Si) exposure, at doses of 1 Gy or less, have been shown to be 50-fold
more effective at inducing hepatocellular carcinomas (HCC) in C3H/HeJ mice. Furthermore, these tumors
appear to be of a more aggressive phenotype than low LET radiation-induced tumors. We have used this
model to determine the underlying signal transduction that may drive this aggressive phenotype through
both mRNA and miRNA expression profiling. We also examined circulating miRNA in tumor-bearing mice
and compared them to previously published miRNA expression profiles in human HCC. C3H mice were
exposed to increasing doses of 56Fe, 28Si and γ-rays. Liver samples were collected at 15 weeks or 12
months after irradiation. Gene expression profiling was performed using Illumina Whole Genome
Expression Arrays on specimens from HCC found in irradiated animals or from spontaneous HCC,
specimens from irradiated mice that did not form HCC and on specimens from unirradiated control
animals. miRNA profiling was performed in the same cohort of mice using Exiqon miRNA arrays.
Unsupervised clustering analysis of both gene expression and miRNA profiling separated specimens into
2 groups, HCC and non-HCC. Within each group, there was no clear distinction between specimens from
irradiated vs. non-irradiated samples. Significance analysis identified 2576 genes that were differentially
expressed between HCC and normal liver specimens (FDR < 0.01). Cancer and Inflammatory response
were among the top gene function categories while Apoptosis Signaling and Acute Phase Inflammatory
Response were among signaling pathways associated with HCC. Supervised expression analysis revealed
790 genes that exhibited distinct expression patterns in spontaneous HCC or HCC induced by different
radiation types. MiRNA analysis revealed 132 miRNAs that were differentially expressed in HCC (FDR <
0.01). There were commonalities with human HCC associated miRNAs, especially for non-cirrhotic cancer.
These included miR-21, miR-26 and the let-7 family. Preliminary analysis on circulating miRNA of tumor-
bearing mice identified a significant overlap with miRNAs from tissue. We are currently examining the
potential for circulating miRNA as early detectors of disease as a function of time after irradiation. This
study is supported by NASA NSCOR NNX09AM08G.
140 | P a g e
the thermodynamic and stoichiometric characteristics of metabolites were jointly optimized using a
constraint-based approach and mixed integer programming. We will present the data that was used in
the development of the network model and data that support the predictions of the model in relation to
the response to radiation or Erlotinib treatment. These include data demonstrating a mechanistic
connection between increased reactive oxygen species (ROS), cellular bioenergetics, lipid metabolism and
response to radiation and Erlotinib treatment. Understanding the underlying mechanisms associated with
response to radiation and drug targeted therapies will provide new insight to how HNSCC cells acquire
resistance to current therapy treatments and new clinical targets for treatment of radiation-resistant
HNSCC.
(PS2-08) Transcriptome and miRNA profiling of radiation-induced murine HCC in tissues and plasma.
2
1
2
4
3
Lianghao Ding ; Yongjia Yu, PhD ; Robert L. Ullrich ; Michael M. Weil ; Andrew Ray ; and Michael D. Story, 1
1
The University of Texas Southwestern Medical Center, Dallas, TX ; The University of Texas Medical Branch,
4
2
3
Galveston, TX ; Colorado State University, Fort Collins, CO ; and Colorado State University, Fot Colins, CO
HZE particle (56Fe and 28Si) exposure, at doses of 1 Gy or less, have been shown to be 50-fold
more effective at inducing hepatocellular carcinomas (HCC) in C3H/HeJ mice. Furthermore, these tumors
appear to be of a more aggressive phenotype than low LET radiation-induced tumors. We have used this
model to determine the underlying signal transduction that may drive this aggressive phenotype through
both mRNA and miRNA expression profiling. We also examined circulating miRNA in tumor-bearing mice
and compared them to previously published miRNA expression profiles in human HCC. C3H mice were
exposed to increasing doses of 56Fe, 28Si and γ-rays. Liver samples were collected at 15 weeks or 12
months after irradiation. Gene expression profiling was performed using Illumina Whole Genome
Expression Arrays on specimens from HCC found in irradiated animals or from spontaneous HCC,
specimens from irradiated mice that did not form HCC and on specimens from unirradiated control
animals. miRNA profiling was performed in the same cohort of mice using Exiqon miRNA arrays.
Unsupervised clustering analysis of both gene expression and miRNA profiling separated specimens into
2 groups, HCC and non-HCC. Within each group, there was no clear distinction between specimens from
irradiated vs. non-irradiated samples. Significance analysis identified 2576 genes that were differentially
expressed between HCC and normal liver specimens (FDR < 0.01). Cancer and Inflammatory response
were among the top gene function categories while Apoptosis Signaling and Acute Phase Inflammatory
Response were among signaling pathways associated with HCC. Supervised expression analysis revealed
790 genes that exhibited distinct expression patterns in spontaneous HCC or HCC induced by different
radiation types. MiRNA analysis revealed 132 miRNAs that were differentially expressed in HCC (FDR <
0.01). There were commonalities with human HCC associated miRNAs, especially for non-cirrhotic cancer.
These included miR-21, miR-26 and the let-7 family. Preliminary analysis on circulating miRNA of tumor-
bearing mice identified a significant overlap with miRNAs from tissue. We are currently examining the
potential for circulating miRNA as early detectors of disease as a function of time after irradiation. This
study is supported by NASA NSCOR NNX09AM08G.
140 | P a g e
