Environmental Carcinogenesis Division, National Health Effects and Environmental Research Laboratory, US Environmental Protection Agency, Research Triangle Park, USA.
Cancer Cell Int. 2010 Feb 23;10:4. doi: 10.1186/1475-2867-10-4.
Simian Virus 40 (SV40) immortalization followed by treatment of cells with 3-methylcholanthrene (3-MC) has been used to elicit tumors in athymic mice. 3-MC carcinogenesis has been thoroughly studied, however gene-level interactions between 3-MC and SV40 that could have produced the observed tumors have not been explored. The commercially-available human uroepithelial cell lines were either SV40-immortalized (HUC) or SV40-immortalized and then 3-MC-transformed (HUC-TC).
To characterize the SV40 - 3MC interaction, we compared human gene expression in these cell lines using a human cancer array and confirmed selected changes by RT-PCR. Many viral Large T Antigen (Tag) expression-related changes occurred in HUC-TC, and it is concluded that SV40 and 3-MC may act synergistically to transform cells. Changes noted in IFP 9-27, 2'-5' OAS, IF 56, MxA and MxAB were typical of those that occur in response to viral exposure and are part of the innate immune response. Because interferon is crucial to innate immune host defenses and many gene changes were interferon-related, we explored cellular growth responses to exogenous IFN-gamma and found that treatment impeded growth in tumor, but not immortalized HUC on days 4 - 7. Cellular metabolism however, was inhibited in both cell types. We conclude that IFN-gamma metabolic responses were functional in both cell lines, but IFN-gamma anti-proliferative responses functioned only in tumor cells.
Synergism of SV40 with 3-MC or other environmental carcinogens may be of concern as SV40 is now endemic in 2-5.9% of the U.S. population. In addition, SV40-immortalization is a generally-accepted method used in many research materials, but the possibility of off-target effects in studies carried out using these cells has not been considered. We hope that our work will stimulate further study of this important phenomenon.
猿猴病毒 40（SV40）永生化，然后用 3-甲基胆蒽（3-MC）处理细胞，已被用于在无胸腺小鼠中引发肿瘤。3-MC 致癌作用已得到深入研究，但是 3-MC 和 SV40 之间的基因水平相互作用可能导致了观察到的肿瘤，尚未得到探索。市售的人尿上皮细胞系要么是 SV40 永生化的（HUC），要么是 SV40 永生化然后 3-MC 转化的（HUC-TC）。
为了表征 SV40-3MC 相互作用，我们使用人类癌症阵列比较了这些细胞系中的人类基因表达，并通过 RT-PCR 证实了选定的变化。在 HUC-TC 中发生了许多病毒大 T 抗原（Tag）表达相关的变化，因此可以得出结论，SV40 和 3-MC 可能协同作用转化细胞。IFP 9-27、2'-5' OAS、IF 56、MxA 和 MxAB 中注意到的变化是对病毒暴露的典型反应，是先天免疫反应的一部分。因为干扰素对于先天免疫宿主防御至关重要，并且许多基因变化与干扰素有关，所以我们探索了细胞对外源性 IFN-γ的生长反应，发现治疗在第 4-7 天抑制了肿瘤，但没有抑制永生化的 HUC 的生长。然而，两种细胞类型的细胞代谢都受到抑制。我们得出结论，IFN-γ代谢反应在两种细胞系中都是功能性的，但是 IFN-γ抗增殖反应仅在肿瘤细胞中起作用。
SV40 与 3-MC 或其他环境致癌物的协同作用可能令人担忧，因为 SV40 现在在美国人群中流行 2-5.9%。此外，SV40 永生化是一种在许多研究材料中广泛使用的方法，但是在使用这些细胞进行的研究中，脱靶效应的可能性尚未得到考虑。我们希望我们的工作将进一步激发对这一重要现象的研究。
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