Transcriptomic profiling of gamma ray induced mutants from the CGL1 human hybrid cell system reveals novel insights into the mechanisms of radiation-induced carcinogenesis

Jake Pirkkanen, Sujeenthar Tharmalingam, Igor H. Morais, Daniel Lam-Sidun, Christopher Thome, Andrew M. Zarnke, Laura V. Benjamin, Adam C. Losch, Anthony J. Borgmann, Helen Chin Sinex, Marc S. Mendonca, Douglas R. Boreham

Research output: Contribution to journalArticle

Abstract

Background: Somatic cell hybrid systems generated by combining cancerous with non-cancerous cells provide useful model systems to study neoplastic transformation. Combined with recent advances in omics-based technologies, novel molecular signatures that drive radiation-induced carcinogenesis can be analyzed at an exceptional global level. Methods: Here, we present a complete whole-transcriptome analysis of gamma-induced mutants (GIM) and gamma irradiated control (CON) segregants isolated from the CGL1 (HeLa x normal fibroblast) human hybrid cell-system exposed to high doses of radiation. Using the Human Transcriptome Array 2.0 microarray technology and conservative discrimination parameters, we have elucidated 1067 differentially expressed genes (DEGs) between tumorigenic and non-tumorigenic cells. Results: Gene ontology enrichment analysis revealed that tumorigenic cells demonstrated shifts in extracellular matrix (ECM) and cellular adhesion profiles, dysregulation of cyclic AMP (cAMP) signaling, and alterations in nutrient transport and cellular energetics. Furthermore, putative upstream master regulator analysis demonstrated that loss of TGFβ1 signaling due to reduced SMAD3 expression is involved in radiation-induced carcinogenesis. Conclusions: Taken together, this study presents novel insights into specific gene expression and pathway level differences that contribute to radiation-induced carcinogenesis in a human cell-based model. This global transcriptomic analysis and our published tumor suppressor gene deletion loci analyses will allow us to identify and functionally test candidate nexus upstream tumor suppressor genes that are deleted or silenced after exposure to radiation.

Original languageEnglish (US)
Pages (from-to)300-311
Number of pages12
JournalFree Radical Biology and Medicine
Volume145
DOIs
StatePublished - Dec 2019

Fingerprint

Hybrid Cells
Gamma Rays
Gamma rays
Carcinogenesis
Radiation
Genes
Tumor Suppressor Genes
Tumors
Technology
Gene Ontology
Gene Deletion
Gene Expression Profiling
Transcriptome
Cyclic AMP
Extracellular Matrix
Fibroblasts
Microarrays
Hybrid systems
Gene expression
Nutrients

Keywords

  • Cancer
  • Carcinogenesis
  • CGL1 cells
  • Fibroblast
  • Gene expression profiling
  • HeLa
  • Hybrid cells
  • Microarray
  • Radiation
  • Transcriptomics
  • Tumorigenesis

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

Cite this

Transcriptomic profiling of gamma ray induced mutants from the CGL1 human hybrid cell system reveals novel insights into the mechanisms of radiation-induced carcinogenesis. / Pirkkanen, Jake; Tharmalingam, Sujeenthar; Morais, Igor H.; Lam-Sidun, Daniel; Thome, Christopher; Zarnke, Andrew M.; Benjamin, Laura V.; Losch, Adam C.; Borgmann, Anthony J.; Sinex, Helen Chin; Mendonca, Marc S.; Boreham, Douglas R.

In: Free Radical Biology and Medicine, Vol. 145, 12.2019, p. 300-311.

Research output: Contribution to journalArticle

Pirkkanen, Jake ; Tharmalingam, Sujeenthar ; Morais, Igor H. ; Lam-Sidun, Daniel ; Thome, Christopher ; Zarnke, Andrew M. ; Benjamin, Laura V. ; Losch, Adam C. ; Borgmann, Anthony J. ; Sinex, Helen Chin ; Mendonca, Marc S. ; Boreham, Douglas R. / Transcriptomic profiling of gamma ray induced mutants from the CGL1 human hybrid cell system reveals novel insights into the mechanisms of radiation-induced carcinogenesis. In: Free Radical Biology and Medicine. 2019 ; Vol. 145. pp. 300-311.
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abstract = "Background: Somatic cell hybrid systems generated by combining cancerous with non-cancerous cells provide useful model systems to study neoplastic transformation. Combined with recent advances in omics-based technologies, novel molecular signatures that drive radiation-induced carcinogenesis can be analyzed at an exceptional global level. Methods: Here, we present a complete whole-transcriptome analysis of gamma-induced mutants (GIM) and gamma irradiated control (CON) segregants isolated from the CGL1 (HeLa x normal fibroblast) human hybrid cell-system exposed to high doses of radiation. Using the Human Transcriptome Array 2.0 microarray technology and conservative discrimination parameters, we have elucidated 1067 differentially expressed genes (DEGs) between tumorigenic and non-tumorigenic cells. Results: Gene ontology enrichment analysis revealed that tumorigenic cells demonstrated shifts in extracellular matrix (ECM) and cellular adhesion profiles, dysregulation of cyclic AMP (cAMP) signaling, and alterations in nutrient transport and cellular energetics. Furthermore, putative upstream master regulator analysis demonstrated that loss of TGFβ1 signaling due to reduced SMAD3 expression is involved in radiation-induced carcinogenesis. Conclusions: Taken together, this study presents novel insights into specific gene expression and pathway level differences that contribute to radiation-induced carcinogenesis in a human cell-based model. This global transcriptomic analysis and our published tumor suppressor gene deletion loci analyses will allow us to identify and functionally test candidate nexus upstream tumor suppressor genes that are deleted or silenced after exposure to radiation.",
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T1 - Transcriptomic profiling of gamma ray induced mutants from the CGL1 human hybrid cell system reveals novel insights into the mechanisms of radiation-induced carcinogenesis

AU - Pirkkanen, Jake

AU - Tharmalingam, Sujeenthar

AU - Morais, Igor H.

AU - Lam-Sidun, Daniel

AU - Thome, Christopher

AU - Zarnke, Andrew M.

AU - Benjamin, Laura V.

AU - Losch, Adam C.

AU - Borgmann, Anthony J.

AU - Sinex, Helen Chin

AU - Mendonca, Marc S.

AU - Boreham, Douglas R.

PY - 2019/12

Y1 - 2019/12

N2 - Background: Somatic cell hybrid systems generated by combining cancerous with non-cancerous cells provide useful model systems to study neoplastic transformation. Combined with recent advances in omics-based technologies, novel molecular signatures that drive radiation-induced carcinogenesis can be analyzed at an exceptional global level. Methods: Here, we present a complete whole-transcriptome analysis of gamma-induced mutants (GIM) and gamma irradiated control (CON) segregants isolated from the CGL1 (HeLa x normal fibroblast) human hybrid cell-system exposed to high doses of radiation. Using the Human Transcriptome Array 2.0 microarray technology and conservative discrimination parameters, we have elucidated 1067 differentially expressed genes (DEGs) between tumorigenic and non-tumorigenic cells. Results: Gene ontology enrichment analysis revealed that tumorigenic cells demonstrated shifts in extracellular matrix (ECM) and cellular adhesion profiles, dysregulation of cyclic AMP (cAMP) signaling, and alterations in nutrient transport and cellular energetics. Furthermore, putative upstream master regulator analysis demonstrated that loss of TGFβ1 signaling due to reduced SMAD3 expression is involved in radiation-induced carcinogenesis. Conclusions: Taken together, this study presents novel insights into specific gene expression and pathway level differences that contribute to radiation-induced carcinogenesis in a human cell-based model. This global transcriptomic analysis and our published tumor suppressor gene deletion loci analyses will allow us to identify and functionally test candidate nexus upstream tumor suppressor genes that are deleted or silenced after exposure to radiation.

AB - Background: Somatic cell hybrid systems generated by combining cancerous with non-cancerous cells provide useful model systems to study neoplastic transformation. Combined with recent advances in omics-based technologies, novel molecular signatures that drive radiation-induced carcinogenesis can be analyzed at an exceptional global level. Methods: Here, we present a complete whole-transcriptome analysis of gamma-induced mutants (GIM) and gamma irradiated control (CON) segregants isolated from the CGL1 (HeLa x normal fibroblast) human hybrid cell-system exposed to high doses of radiation. Using the Human Transcriptome Array 2.0 microarray technology and conservative discrimination parameters, we have elucidated 1067 differentially expressed genes (DEGs) between tumorigenic and non-tumorigenic cells. Results: Gene ontology enrichment analysis revealed that tumorigenic cells demonstrated shifts in extracellular matrix (ECM) and cellular adhesion profiles, dysregulation of cyclic AMP (cAMP) signaling, and alterations in nutrient transport and cellular energetics. Furthermore, putative upstream master regulator analysis demonstrated that loss of TGFβ1 signaling due to reduced SMAD3 expression is involved in radiation-induced carcinogenesis. Conclusions: Taken together, this study presents novel insights into specific gene expression and pathway level differences that contribute to radiation-induced carcinogenesis in a human cell-based model. This global transcriptomic analysis and our published tumor suppressor gene deletion loci analyses will allow us to identify and functionally test candidate nexus upstream tumor suppressor genes that are deleted or silenced after exposure to radiation.

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KW - Fibroblast

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