Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Transcription profiling of human HPV-immortalized keratinocytes

ABSTRACT: To identify early processes in carcinogenesis, we used an in vitro model, based on the initiating event in cervical cancer, human papillomavirus (HPV) transformation of keratinocytes. We compared gene expression in primary keratinocytes (K) and HPV16-transformed keratinocytes from early (E) and late (L) passages, and from benzo[a]pyrene treated L cells (BP). The transformed cells exhibit similar transcriptional changes to clinical cervical carcinoma. We revealed a contraction in expression of the apoptotic network during HF1 cell transformation, which affected the ability of L and BP cells to execute apoptosis, but did not lead to resistance to apoptotic stimuli. The contraction in the apoptotic machinery during the process of transformation was accompanied by a switch from apoptosis to necrosis in response to CDDP. The shrinkage of the pro- and anti-apoptotic networks appears to be part of a general contraction in the number of genes transcribed in L and BP cells. We also identified a large group of genes with induced expression, which are involved in cell metabolism and cell cycle, suggesting increased investment of the transformed cell in cellular proliferation. We hypothesize that the decrease in expression of many diverse pathways, including the pro- and anti-apoptotic networks, cuts the energy requirements for cell maintenance, allowing energy to be diverted towards rapid cell proliferation. This study supports the hypothesis that the process of cancer transformation may be accompanied by a shift from apoptosis to necrosis. Experiment Overall Design: We isolated mRNA from three independent cultures each of Keratinocytes and HPV16-immortalized keratinocytes : E, L and BP cells, grown under basal conditions. cDNA was prepared and hybridized to the Human Genome U133A Array (Affymetrix).

ORGANISM(S): Homo sapiens

SUBMITTER: Alexander Levitzki

PROVIDER: E-GEOD-15156 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Shift from apoptotic to necrotic cell death during human papillomavirus-induced transformation of keratinocytes.

Kravchenko-Balasha Nataly N Mizrachy-Schwartz Sarit S Klein Shoshana S Levitzki Alexander A

The Journal of biological chemistry 20090216 17

Oncogenic transformation is a complex, multistep process, which goes through several stages before complete malignant transformation occurs. To identify early processes in carcinogenesis, we used an in vitro model, based on the initiating event in cervical cancer, papillomavirus transformation of keratinocytes. We compared gene expression in primary keratinocytes (K) and papillomavirus-transformed keratinocytes from early (E) and late (L) passages and from benzo[a]pyrene-treated L cells (BP). Th ...[more]

PMID: 19221178

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Project description:Glucocorticoids (GCs) have a long history of use as therapeutic agents for numerous skin diseases. Surprisingly, their specific molecular effects are largely unknown. To characterize GC action in epidermis, we compared the transcriptional profiles of primary human keratinocytes untreated and treated with dexamethasone (DEX) for 1, 4, 24, 48 and 72 hours using large-scale microarray analyses. The majority of genes were found regulated only after 24 hours and remained regulated throughout the treatment. In addition to expected anti-inflammatory genes, we found that GCs regulate cell fate, tissue remodeling, cell motility, differentiation and metabolism. GCs not only effectively block signaling by TNF-alpha and IL-1 but also by IFN-gamma, which was not previously known. Specifically, GCs suppress the expression of essentially all IFN-gamma-regulated genes, including IFN-gamma receptor and STAT-1. GCs also block STAT-1 activation and nuclear translocation. Unexpectedly, GCs have anti-apoptotic effects in keratinocytes by inducing the expression of anti-apoptotic and repressing pro-apoptotic genes. Consequently, GCs treatment blocked UV-induced apoptosis of keratinocytes. GCs have a profound effect on wound healing by inhibiting cell motility and the expression of pro-angiogenic factor VEGF. They play an important role in tissue remodeling and scar formation by suppressing the expression of TGF-beta-1 and -2, MMP1, 2, 9 and 10 and inducing TIMP-2. Finally, GCs promote terminal stages of epidermal differentiation while simultaneously inhibiting the early stages. These results provide new insights into the beneficial and adverse effects of GCs in epidermis, defining the participating genes and mechanisms that coordinate the cellular responses important for GC-based therapies. Human epidermal keratinocytes are grown in delipidized, phenolphtalein-free medium and left as controls or treated with 0.1μM dexamethasone. Time course of treated and parallel control samples over a 72 hr period was performed twice with independent batches of cells.

Dataset Information

Transcription profiling of human HPV-immortalized keratinocytes

Publications

Shift from apoptotic to necrotic cell death during human papillomavirus-induced transformation of keratinocytes.

Similar Datasets

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