Barboro P, Alberti I, Sanna P, Parodi S, Balbi C, Allera C, Patrone E
Istituto Nazionale per la Ricerca sul Cancro, Largo Rosanna Benzi, Genoa, Italy.
Exp Cell Res. 1996 Jun 15;225(2):315-27. doi: 10.1006/excr.1996.0182.
In a previous paper (Barboro et al., 1993, Biophys. J. 65, 1690-1699) we have shown that cancer development in the resistant hepatocyte model of Solt and Farber is characterized by the progressive unfolding of the higher-order structure of chromatin. A possible functional role of decondensation phenomena in cell transformation cannot be ruled out. Genetic activation involves the relaxation of the superstructure of chromatin, which may be, at least in part, modulated by its interaction with the nuclear matrix. Moreover, recent observations suggest that gene expression can be stimulated by alterations in the organization of the cytoskeleton. Therefore, we have characterized the changes in composition that the nuclear matrix-intermediate filament complex undergoes during the evolution of rat hepatocyte nodules. Dramatic changes in the expression of both the nuclear matrix and intermediate filament proteins occur during transformation; they are, however, related in a different way to the stages of carcinogenesis. Several new nuclear matrix proteins appear in early nodules, isolated 9 weeks after initiation. The subsequent evolution of persistent nodules is also characterized by discrete changes in the composition. Thus, the new synthesis of nuclear matrix proteins reflects the emergence of successive cellular populations, in line with the recent finding that a subset of components of the nuclear matrix is cell type-specific. In contrast, intermediate filament proteins undergo continuing changes. A new keratin with apparent molecular weight of 39 kDa, analogous to human keratin 19, appears in early nodules, and its expression steadily increases up to the 32nd week from initiation; at the same time, the amount of the proteolytic fragments of keratins A and D increases sharply. These findings suggest that the inappropriate expression of keratin 19 may be involved in the epigenetic activation of new cellular programs, through the rearrangement of the cytoskeleton which in turn may perturb nuclear matrix function.
在之前的一篇论文中（Barboro等人，1993年，《生物物理学杂志》65卷，1690 - 1699页），我们已经表明，索尔和法伯的抗性肝细胞模型中的癌症发展特征是染色质高阶结构的逐步展开。去浓缩现象在细胞转化中可能的功能作用不能被排除。基因激活涉及染色质超结构的松弛，这可能至少部分地由其与核基质的相互作用调节。此外，最近的观察表明，细胞骨架组织的改变可以刺激基因表达。因此，我们已经描述了大鼠肝结节演变过程中核基质 - 中间丝复合物在组成上的变化。在转化过程中，核基质和中间丝蛋白的表达都发生了显著变化；然而，它们与致癌阶段的关系方式不同。在启动9周后分离出的早期结节中出现了几种新的核基质蛋白。持续结节的后续演变也以组成上的离散变化为特征。因此，核基质蛋白的新合成反映了连续细胞群体的出现，这与最近发现核基质的一部分成分是细胞类型特异性的一致。相比之下，中间丝蛋白经历持续变化。一种表观分子量为39 kDa的新角蛋白，类似于人角蛋白19，出现在早期结节中，其表达从启动开始到第32周稳步增加；同时，角蛋白A和D的蛋白水解片段的量急剧增加。这些发现表明，角蛋白19的不适当表达可能通过细胞骨架的重排参与新细胞程序的表观遗传激活，而细胞骨架重排反过来可能扰乱核基质功能。
