Refractory nature of normal human diploid fibroblasts with respect to oncogene-mediated transformation
Refractory nature of normal human diploid fibroblasts with respect to oncogene-mediated transformation
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DOI：
10.1073/pnas.1834876100
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发表时间：
2003-11-11
影响因子：
11.1
通讯作者：
Hanafusa, H
中科院分区：
文献类型：
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作者：
Akagi, T;Sasai, K;Hanafusa, H
已知人类细胞比啮齿动物细胞在体外更难抵抗致癌转化。迄今为止，这种耐药性的分子机制在很大程度上仍然未知。猴病毒40早期区和H-Ras V12的组合对大鼠胚胎成纤维细胞的转化有效，但对人细胞无效。然而，端粒酶催化亚单位（hTERT）的额外异位表达被报道能够引起正常人类细胞的转化。然而，在这项研究中，我们证明了上述三种遗传因子的联合表达并不总是足以转化正常的人二倍体成纤维细胞（HDF）。虽然这些导入的遗传元件的表达和功能基本相同，但在四种HDF中，TIG-1和TIG-3对转化具有抗性。另外两种细胞（BJ和IMR-90）表现出转化表型，但与大鼠胚胎成纤维细胞相比，它们在表达猴病毒40早期区和H-Ras V12方面受到很大限制。与这些表型相关，TIG-1和TIG-3在引入这些遗传元件后保持二倍体，而BJ和IMR-90变成高度非整倍体。这些结果有力地表明，端粒酶的缺乏不是HDF抵抗转化的难治性的唯一原因，并且正常人细胞仍然具有不确定的内在机制，使其对致癌转化具有抗性。
Human cells are known to be more refractory than rodent cells against oncogenic transformation in vitro. To date, the molecular mechanisms underlying such resistance remain largely unknown. The combination of simian virus 40 early region and H-Ras V12 has been effective for transformation of rat embryo fibroblasts, but not for human cells. However, the additional ectopic expression of the telomerase catalytic subunit (hTERT) was reported to be capable of causing transformation of normal human cells. In this study, however, we demonstrate that the combined expression of the above-mentioned three genetic elements is not always sufficient to transform normal human diploid fibroblasts (HDF). Although the expression and function of these introduced genetic elements were essentially the same, among four HDF, TIG-1 and TIG-3 were resistant to transformation. The other two (BJ and IMR-90) showed transformed phenotypes, but they were much restricted compared with rat embryo fibroblasts in expressing simian virus 40 early region and H-Ras V12. In correlation with these phenotypes, TIG-1 and TIG-3 remained diploid after the introduction of these genetic elements, whereas BJ and IMR-90 became highly aneuploid. These results strongly suggest that the lack of telomerase is not the sole reason for the refractory nature of HDF against transformation and that normal human cells have still undefined intrinsic mechanisms rendering them resistant to oncogenic transformation.