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A malignant transformation of human cells by 2,3,7,8-tetrachlorodibenzo-p-dioxin exhibits altered expressions of growth regulatory factors
Department of Pharmacology and Toxicology, School of Medicine, Catholic University of Taegu-Hyosung, 3056-6 Taemyong-4-dong, Namgu, Taegu 705-034, Korea and
1 Department of Toxicology, Medical Institute of Environmental Hygiene at the Heinrich-Heine University of Dusseldorf, Dusseldorf, Germany
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-ß1 (TGF-ß1), plasminogen activator inhibitor-2 (PAI-2) and tumor necrosis factor-
(TNF-), 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-ß1 mRNA in the transformed cells was also four times lower than the parental cells. However, levels of TNF- 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-ß1 or TNF-, 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.
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