Yang J H, Vogel C, Abel J
Department of Pharmacology and Toxicology, School of Medicine, Catholic University of Taegu-Hyosung, Korea.
Carcinogenesis. 1999 Jan;20(1):13-8. doi: 10.1093/carcin/20.1.13.
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-beta1 (TGF-beta1), plasminogen activator inhibitor-2 (PAI-2) and tumor necrosis factor-alpha (TNF-alpha), 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 posttranscriptional control. Expression of TGF-beta1 mRNA in the transformed cells was also four times lower than the parental cells. However, levels of TNF-alpha 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-beta1 or TNF-alpha, 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.
最近有报道称，人类细胞在培养过程中暴露于2,3,7,8-四氯二苯并对二恶英（TCDD）会发生肿瘤转化。在本研究中，分析了生长调节因子的表达，以研究它们在TCDD诱导的人类细胞恶性转化中可能发挥的作用。采用逆转录-聚合酶链反应（RT-PCR）和免疫印迹分析来检测与二恶英反应相关基因的表达变化。RT-PCR分析表明，与亲代细胞相比，转化细胞中生长调节因子的表达发生了显著变化，如转化生长因子-β1（TGF-β1）、纤溶酶原激活物抑制剂-2（PAI-2）和肿瘤坏死因子-α（TNF-α）。亲代细胞在TCDD暴露后PAI-2 mRNA水平呈剂量依赖性增加，而转化细胞未表现出任何显著诱导。此外，转化细胞中PAI-2 mRNA的组成性水平比亲代细胞低25倍。mRNA稳定性分析表明，转化细胞中PAI-2 mRNA的下调可能与转录后调控有关。转化细胞中TGF-β1 mRNA的表达也比亲代细胞低四倍。然而，转化细胞中TNF-α mRNA的水平增加了3倍。这些结果表明，生长调节因子的失调可能参与了TCDD诱导的细胞转化。尽管大量研究证明了TCDD的许多即时毒性作用，但本研究首次表明，生长调节基因如PAI-2、TGF-β1或TNF-α的表达改变是TCDD损伤细胞连续细胞分裂后基因组中固定的一些遗传事件。提示这些变化可能与TCDD诱导的人类细胞恶性转化有关。
