Page 141 - 2014 Printable Abstract Book
P. 141
(PS2-05) Genetic signatures detected in thyroid tissue in mice after 131I and 211At exposure. Nils
Rudqvist; Toshima Z. Parris; Britta Langen; Emil Schüler; Johan Spetz; Khalil Helou; and Eva Forssell-
Aronsson, University of Gothenburg, Gothenburg, Sweden
211
131
211
131
β-emitter I and α-emitter At are used in radionuclide therapy. Unbound I and At accumulate in
the thyroid gland and may be detrimental for normal thyroid function. This was seen after the Chernobyl
131
accident where a release of I to the atmosphere increased the incidence of thyroid cancer in individuals
exposed as children. The radiation-induced effects of 131 I and 211 At in thyroid tissue vary with exposure
condition. However, the relation between exposure condition and induced effects are largely unknown.
131
Forty-four female Balb/c nude mice were i.v. injected with 13, 130, or 260 kBq I or with 1.7, 7.5, or 100
211
kBq At and killed at 1, 6, 24, or 168 h after injection, or mock-treated. Resulting absorbed dose (D) from
131 I exposure was 0.85, 8.5, and 17 Gy at 24 h while 211 At exposure resulted in 0.023 and 1.4 Gy at 1 h;
0.32 and 1.4 Gy for 6 h; 0.05, 0.5, 1.4, 11, and 32 Gy at 24 h, and 1.8 Gy at 168 h. RNA was extracted from
thyroids, pooled within each group, and mRNA levels were determined with Illumina microarray platform.
Gene expression levels and related biological functions were compared with mock-treated controls using
Nexus Expression 3.0. Totally, 1346 unique transcripts were differentially regulated at all exposure
conditions and 13 genes were regulated at ≥10/13 exposure conditions. The S100a8 and S100a9 genes
were regulated at 12/13 and 10/13 exposure conditions, respectively. S100A8 regulates the inflammatory
and immune system, and can together with S100A9 form the heterodimer calprotectin, a biomarker for
inflammatory disease. S100a8 and S100a9 have similar expression patterns in the present study. Clec2d
was regulated at 11/13 exposure conditions (upregulated at higher D, downregulated at lower D). The
Clec2d gene is located in the natural killer (NK) gene complex and the gene product is a ligand for the
NKRP1B receptor and expression of CLEC2D protects cells from NK cell-mediated killing. Furthermore, Klk1
and 12 other Klk1-related peptidases were commonly and similarly regulated. Generally, these genes
were upregulated at high D and late time-points but downregulated at lower D and early time-points. In
211
131
conclusion, exposure to both I and At caused a significant impact on normal thyroid tissue with large
differences in gene expression signature between the investigated exposure conditions.
(PS2-06) Integrated "omics" approach to discover therapies for radiation resistant head and neck
cancer. Jade Mims; Zhiwei Ji; Nelmi O. Devarie-Baez, PhD; Jin Su, PhD; Weiling Zhao, PhD; Glen S. Marrs,
PhD; Mercedes Porosnicu, MD; Allen W. Tsang, PhD; Xiaobo Zhou, PhD; and Cristina M. Furdui, PhD
Wake Forest University School of Medicine, Winston Salem, NC
Head and Neck Squamous Cell Carcinoma (HNSCC) is a complex disease characterized by genetic
and metabolic changes. Despite advancements in therapies over the last two decades, its diversity,
invasiveness and resistance to therapies constitute significant roadblocks for treatment of HNSCC and
overall improvement of patients’ quality of life. Growing evidence is showing that chemical reactions
underlying signaling and metabolism are heavily regulated by cellular reduction and oxidation processes.
To investigate redox-dependent and -independent mechanisms controlling the response to therapies, we
developed a matched cell model of HNSCC characterized by increased resistance to radiation and
increased response to Erlotinib (Trade name Tarceva®), a targeted inhibitor of epidermal growth factor
receptor (EGFR). We present a computational approach that integrates multiple “omics” datasets
collected in this cell-based system into a mathematical model describing the regulatory relationship
among the cellular redox balance, signaling and metabolism, and the response to radiation and Erlotinib.
139 | P a g e
Rudqvist; Toshima Z. Parris; Britta Langen; Emil Schüler; Johan Spetz; Khalil Helou; and Eva Forssell-
Aronsson, University of Gothenburg, Gothenburg, Sweden
211
131
211
131
β-emitter I and α-emitter At are used in radionuclide therapy. Unbound I and At accumulate in
the thyroid gland and may be detrimental for normal thyroid function. This was seen after the Chernobyl
131
accident where a release of I to the atmosphere increased the incidence of thyroid cancer in individuals
exposed as children. The radiation-induced effects of 131 I and 211 At in thyroid tissue vary with exposure
condition. However, the relation between exposure condition and induced effects are largely unknown.
131
Forty-four female Balb/c nude mice were i.v. injected with 13, 130, or 260 kBq I or with 1.7, 7.5, or 100
211
kBq At and killed at 1, 6, 24, or 168 h after injection, or mock-treated. Resulting absorbed dose (D) from
131 I exposure was 0.85, 8.5, and 17 Gy at 24 h while 211 At exposure resulted in 0.023 and 1.4 Gy at 1 h;
0.32 and 1.4 Gy for 6 h; 0.05, 0.5, 1.4, 11, and 32 Gy at 24 h, and 1.8 Gy at 168 h. RNA was extracted from
thyroids, pooled within each group, and mRNA levels were determined with Illumina microarray platform.
Gene expression levels and related biological functions were compared with mock-treated controls using
Nexus Expression 3.0. Totally, 1346 unique transcripts were differentially regulated at all exposure
conditions and 13 genes were regulated at ≥10/13 exposure conditions. The S100a8 and S100a9 genes
were regulated at 12/13 and 10/13 exposure conditions, respectively. S100A8 regulates the inflammatory
and immune system, and can together with S100A9 form the heterodimer calprotectin, a biomarker for
inflammatory disease. S100a8 and S100a9 have similar expression patterns in the present study. Clec2d
was regulated at 11/13 exposure conditions (upregulated at higher D, downregulated at lower D). The
Clec2d gene is located in the natural killer (NK) gene complex and the gene product is a ligand for the
NKRP1B receptor and expression of CLEC2D protects cells from NK cell-mediated killing. Furthermore, Klk1
and 12 other Klk1-related peptidases were commonly and similarly regulated. Generally, these genes
were upregulated at high D and late time-points but downregulated at lower D and early time-points. In
211
131
conclusion, exposure to both I and At caused a significant impact on normal thyroid tissue with large
differences in gene expression signature between the investigated exposure conditions.
(PS2-06) Integrated "omics" approach to discover therapies for radiation resistant head and neck
cancer. Jade Mims; Zhiwei Ji; Nelmi O. Devarie-Baez, PhD; Jin Su, PhD; Weiling Zhao, PhD; Glen S. Marrs,
PhD; Mercedes Porosnicu, MD; Allen W. Tsang, PhD; Xiaobo Zhou, PhD; and Cristina M. Furdui, PhD
Wake Forest University School of Medicine, Winston Salem, NC
Head and Neck Squamous Cell Carcinoma (HNSCC) is a complex disease characterized by genetic
and metabolic changes. Despite advancements in therapies over the last two decades, its diversity,
invasiveness and resistance to therapies constitute significant roadblocks for treatment of HNSCC and
overall improvement of patients’ quality of life. Growing evidence is showing that chemical reactions
underlying signaling and metabolism are heavily regulated by cellular reduction and oxidation processes.
To investigate redox-dependent and -independent mechanisms controlling the response to therapies, we
developed a matched cell model of HNSCC characterized by increased resistance to radiation and
increased response to Erlotinib (Trade name Tarceva®), a targeted inhibitor of epidermal growth factor
receptor (EGFR). We present a computational approach that integrates multiple “omics” datasets
collected in this cell-based system into a mathematical model describing the regulatory relationship
among the cellular redox balance, signaling and metabolism, and the response to radiation and Erlotinib.
139 | P a g e
