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Free Radic Biol Med. 2019 Dec;145:300-311. doi: 10.1016/j.freeradbiomed.2019.09.037. Epub 2019 Sep 30.

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

Author information

1
Laurentian University, 935 Ramsey Lake Rd, Sudbury, Ontario, P3E 2C6, Canada. Electronic address: jpirkkanen@laurentian.ca.
2
Northern Ontario School of Medicine, 935 Ramsey Lake Rd, Sudbury, Ontario, P3E 2C6, Canada. Electronic address: sujeenthar@rogers.com.
3
Laurentian University, 935 Ramsey Lake Rd, Sudbury, Ontario, P3E 2C6, Canada. Electronic address: igorhmorais@gmail.com.
4
Northern Ontario School of Medicine, 935 Ramsey Lake Rd, Sudbury, Ontario, P3E 2C6, Canada. Electronic address: daniel_lam-sidun@live.ca.
5
Northern Ontario School of Medicine, 935 Ramsey Lake Rd, Sudbury, Ontario, P3E 2C6, Canada. Electronic address: cthome@nosm.ca.
6
Laurentian University, 935 Ramsey Lake Rd, Sudbury, Ontario, P3E 2C6, Canada. Electronic address: azarnke@laurentian.ca.
7
Department of Radiation Oncology, Radiation and Cancer Biology Laboratories, Department of Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA. Electronic address: lauravbenjamin@gmail.com.
8
Department of Radiation Oncology, Radiation and Cancer Biology Laboratories, Department of Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA. Electronic address: aclosch@gmail.com.
9
Department of Radiation Oncology, Radiation and Cancer Biology Laboratories, Department of Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA. Electronic address: tony.borgmann@gmail.com.
10
Department of Radiation Oncology, Radiation and Cancer Biology Laboratories, Department of Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA. Electronic address: hjchin@iupui.edu.
11
Department of Radiation Oncology, Radiation and Cancer Biology Laboratories, Department of Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA. Electronic address: mmendonc@iupui.edu.
12
Northern Ontario School of Medicine, 935 Ramsey Lake Rd, Sudbury, Ontario, P3E 2C6, Canada; Bruce Power, PO Box 1540, 177 Tie Rd, R.R. 2, Tiverton, Ontario, N0G 2T0, Canada. Electronic address: dboreham@nosm.ca.

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.

KEYWORDS:

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

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