Journal Article

Substantial changes in gene expression of Wnt, MAPK and TNFα pathways induced by TGF-β1 in cervical cancer cell lines

Judith N. Kloth, Gert Jan Fleuren, Jan Oosting, Renee X. de Menezes, Paul H.C. Eilers, Gemma G. Kenter and Arko Gorter

in Carcinogenesis

Volume 26, issue 9, pages 1493-1502
Published in print September 2005 | ISSN: 0143-3334
Published online May 2005 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgi110
Substantial changes in gene expression of Wnt, MAPK and TNFα pathways induced by TGF-β1 in cervical cancer cell lines

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Transforming growth factor-beta 1 (TGF-β1) is a potent inhibitor of epithelial cell proliferation. During the development of cervical carcinoma however, an increase in production of TGF-β1 is accompanied by decreased sensitivity for the growth-limiting effect of TGF-β1. TGF-β1 has an anti-proliferative effect on cells of the immune system and thus can be advantageous for tumor progression. The aim of the present study was to determine the effect of TGF-β1 on mRNA expression profile of genes in pathways involved in cell growth and cell death, in cervical carcinoma cell lines with different sensitivity to TGF-β1. For this purpose, we have investigated changes in gene expression in TGF-β1 stimulated cervical cancer cell lines with high (CC10B), intermediate (SiHa) and low (HeLa) sensitivity to the anti-proliferative effect of TGF-β1, at timepoints 0, 6, 12 and 24 h. Microarray analysis, using Affymetrics focus arrays, representing 8973 genes, was used to measure gene expression. In our study novel target genes involved in tumor necrosis factor alpha (TNFα), mitogen-activated protein kinase (MAPK) and wingless type (Wnt) pathways in response to TGF-β1 were found. Substantial differences in gene expression between TGF-β1 sensitive and insensitive cell lines were observed involving genes in TNFα, MAPK, Wnt and Smad pathways. Since these pathways are implicated in cell proliferation and cell death, these pathways may play a role in determining the overall sensitivity of a cell to TGF-β1 induced cell growth inhibition. The results were subsequently validated by quantitative real-time PCR. Increased resistance to TGF-β1 induced cell growth inhibition was correlated with an elevated production of TGF-β1 by the cell lines, as measured by enzyme linked immunosorbent assay. TGF-β1 production did not inhibit cell growth, since blocking TGF-β1 protein by anti-TGF-β had no effect on cell proliferation. TGF-β1 excretion by tumor cells more likely contributes to paracrine stimulation of tumor development.

Keywords: AffyPLM, Affy-Probe Level Model; CDK, cyclin dependent kinase; ECM, extracellular matrix; EGF, epidermal growth factor; EMT, epithelial to mesenchym transition; ERK, extracellular response kinase; FGF, fibroblast growth factor; GO, gene ontology; IFNγ, interferonγ; MAPK, mitogen-activated protein kinases; NFκB, nuclear factor kappa B; PI3K, phosphatidylinositol-3 kinase; QRT–PCR, quantitative real-time PCR; RMA, Robust Multi-Chip Average; SAPK, stress activated protein kinase; SSCG, statistically significant changes in gene expression; TGF-β1, transforming growth factor β1; TNFα, tumor necrosis factor α; Wnt, wingless type

Journal Article.  5759 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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