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

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. 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. 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. 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. Image 1 • Whole transcriptome and gene ontology enrichment analysis was performed on independently isolated radiation-induced tumorigenic segregants of CGL1 human hybrid cells (GIMs) versus irradiated but nontumorigenic CONs. Radiation-induced carcinogenesis resulted in: • Shifts in extracellular matrix, cellular adhesion, cyclic AMP signaling, nutrient transport and cellular energetics now classified as hallmarks of cancer. • Loss of TGF-β1 signaling due to reduced SMAD3 expression. • Changes in gene expression that agreed with extensive published phenotypic alterations observed in these radiation-induced tumorigenic GIM segregants. • Identification specific gene expression and pathway level differences that contribute to radiation-induced carcinogenesis in a human cell-based model. • Global transcriptomic and tumor suppressor gene deletion loci analyses will allow us to functionally test candidate nexus upstream tumor suppressor genes involved in radiation carcinogenesis. [ABSTRACT FROM AUTHOR]