Abstract
BackgroundCells transformed by human adenoviruses (Ad) exhibit differential capacities to induce tumours in immunocompetent rodents; for example, Ad12-transformed rodent cells are oncogenic whereas Ad5-transformed cells are not. The E1A gene determines oncogenic phenotype, is a transcriptional regulator and dysregulates host cell gene expression, a key factor in both cellular transformation and oncogenesis. To reveal differences in gene expression between cells transformed with oncogenic and non-oncogenic adenoviruses we have performed comparative analysis of transcript profiles with the aim of identifying candidate genes involved in the process of neoplastic transformation.ResultsAnalysis of microarray data revealed that a total of 232 genes were differentially expressed in Ad12 E1- or Ad5 E1-transformed BRK cells compared to untransformed baby rat kidney (BRK) cells. Gene information was available for 193 transcripts and using gene ontology (GO) classifications and literature searches it was possible to assign known or suggested functions to 166 of these identified genes. A subset of differentially-expressed genes from the microarray was further examined by real-time PCR and Western blotting using BRK cells immortalised by Ad12 E1A or Ad5 E1A in addition to Ad12 E1- or Ad5 E1-transformed BRK cells. Up-regulation of RelA and significant dysregulation of collagen type I mRNA transcripts and proteins were found in Ad-transformed cells.ConclusionThese results suggest that a complex web of cellular pathways become altered in Ad-transformed cells and that Ad E1A is sufficient for the observed dysregulation. Further work will focus on investigating which splice variant of Ad E1A is responsible for the observed dysregulation at the pathway level, and the mechanisms of E1A-mediated transcriptional regulation.
Highlights
Cells transformed by human adenoviruses (Ad) exhibit differential capacities to induce tumours in immunocompetent rodents; for example, Ad12-transformed rodent cells are oncogenic whereas Ad5-transformed cells are not
Expression ratios of tgDNA between duplicate samples was consistent with good reproducibility and genes whose expression ratio was greater than ± 1.2 were investigated further
Consistent with previous studies which show cell surface expression of β2-m in Ad12-TC is reduced [13], β2-m was shown by the microarray study to be down-regulated between 1.2- and 1.34-fold in Ad12 E1-TC and is essentially unaltered in Ad5 E1-TC compared to baby rat kidney (BRK) cells
Summary
Cells transformed by human adenoviruses (Ad) exhibit differential capacities to induce tumours in immunocompetent rodents; for example, Ad12-transformed rodent cells are oncogenic whereas Ad5-transformed cells are not. The E1A gene determines oncogenic phenotype, is a transcriptional regulator and dysregulates host cell gene expression, a key factor in both cellular transformation and oncogenesis. All human Ad serotypes can transform primary baby rat kidney (BRK) cells in vitro, only BRK cells transformed by the species A human Ads (such as Ad12) can induce tumour formation in immunocompetent adult rodents [reviewed in [6]]. Investigation of the mechanisms directing such oncogenesis has bestowed a greater understanding of cell cycle control and apoptosis; for example, it is well established that products of Ad E1A and E1B genes target the retinoblastoma gene product (pRb) and p53 genes, respectively [5,6]. Rb and p53 are undoubtedly critical players in cell transformation, in order to gain a better understanding of the extent of changes involved in the process of oncogenesis, the challenge is to understand the extent of dysregulation of all the cellular networks and gain a more thorough insight of how the immune response is avoided
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