Journal Article

A malignant transformation of human cells by 2,3,7,8-tetrachlorodibenzo-<i>p</i>-dioxin exhibits altered expressions of growth regulatory factors

Jae-Ho Yang, Christoph Vogel and Josef Abel

in Carcinogenesis

Volume 20, issue 1, pages 13-18
Published in print January 1999 | ISSN: 0143-3334
Published online January 1999 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/20.1.13
A malignant transformation of human cells by 2,3,7,8-tetrachlorodibenzo-p-dioxin exhibits altered expressions of growth regulatory factors

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The neoplastic transformation of human cells in culture with exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has recently been reported. In this study, expressions of growth regulatory factors were analyzed to examine their possible roles in TCDD-induced malignant transformation of human cells. Reverse transcription–polymerase chain reaction (RT–PCR) and immunoblot analysis were performed to detect altered expressions of genes associated with dioxin responses. The RT–PCR analysis showed that expressions of the growth regulatory factors, such as transforming growth factor-β1 (TGF-β1), plasminogen activator inhibitor-2 (PAI-2) and tumor necrosis factor-α (TNF-α), were significantly changed in the transformed cells as compared with the parental cells. Whereas parental cells showed a dose-dependent increase of PAI-2 mRNA levels following TCDD exposure, the transformed cells did not show any significant induction. In addition, constitutive levels of PAI-2 mRNA were 25 times lower in the transformed cells than in the parental cells. The mRNA stability assay suggests that downregulation of PAI-2 mRNA in the transformed cells may be associated with the post-transcriptional control. Expression of TGF-β1 mRNA in the transformed cells was also four times lower than the parental cells. However, levels of TNF-α mRNA in the transformed cells were increased 3-fold. These results suggest that dysregulation of growth regulatory factors may be involved in TCDD-induced cellular transformation. Whereas plenty of studies demonstrated a number of immediate toxic effects by TCDD, this study revealed an initial evidence that altered expression of growth regulatory genes, such as PAI-2, TGF-β1 or TNF-α, are some of the genetic events fixed in the genome following the successive cell divisions of TCDD-damaged cells. It is suggested that these changes may be associated with TCDD-induced malignant transformation of human cells.

Keywords: AHH, aryl hydrocarbon hydroxylase; AhR, aryl hydrocarbon receptor; ARNT, AhR nuclear translocator; CYP, cytochrome P450; DMEM, Dulbecco's modified essential medium; DMSO, dimethyl sulfoxide; DRE, dioxin responsive element; FBS, fetal bovine serum; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; IL, interleukin; PAI-2, plasminogen activator inhibitor-2; PMSF, phenylmethylsulfonyl fluoride; RT–PCR, reverse transcription–polymerase chain reaction; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TGF, transforming growth factor; TNF, tumor necrosis factor; TPA, phorbol 12-myristate 13-acetate; u-PA, urokinase-type plasminogen activator.

Journal Article.  4885 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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