Knockout of 4.1B triggers malignant transformation in SV40T-immortalized mouse embryo fibroblast cells
Knockout of 4.1B triggers malignant transformation in SV40T-immortalized mouse embryo fibroblast cells
复制标题
敲除 4.1B 会引发 SV40T 永生化小鼠胚胎成纤维细胞的恶性转化
DOI：
10.1002/mc.22515
复制
发表时间：
2017-02-01
影响因子：
4.6
通讯作者：
Liu, Jing
中科院分区：
文献类型：
--
作者：
Wang, Zi;Zhang, Jingxin;Liu, Jing
蛋白质4.1B缺乏可促进肿瘤的发生，但4.1B缺乏是否参与恶性转化尚不清楚。在这项研究中，我们证明了4.1B基因缺失足以转化SV 40 T抗原永生化小鼠胚胎成纤维细胞（iMEFs），这反映在4.1B（-/-）iMEFs在4.1B（+/+）iMEFs生长受限的环境中生长并在裸鼠中形成肿瘤的能力，而4.1B（+/+）iMEFs不能在体内形成肿瘤。组织学检查显示4.1B（-/-）iMEFs产生的肿瘤为具有局部浸润特征的硬纤维瘤。此外，4.1B的缺失显著加速了细胞周期进程，伴随着典型的原癌基因ERK、AKT和G1/S调节途径（p16（INK 4A）-pRb途径）的激活，以及Wnt基因家族的许多成员的上调。特别是，4.1B（-/-）iMEFs表现出β-连环蛋白的核积聚，这是硬纤维瘤的指标，下调E-钙粘蛋白表达和上调snail，zeb 1和波形蛋白表达，表明EMT可能发生在转化的4.1B（-/-）iMEFs中。此外，我们发现4.1B与MEF细胞中的E-cadherin相互作用。因此，我们的研究提供了以前未确定的作用和机制的4.1B在细胞转化。(c)2016 Wiley Periodicals，Inc.
Protein 4.1B deficiency has been found to promote the tumor development; however, whether 4.1B deficiency participates in malignant transformation is unknown. In this study, we demonstrated that 4.1B gene deletion was sufficient to transform SV40T antigen-immortalized mouse embryonic fibroblasts (iMEFs), as reflected by the ability of 4.1B(-/-)iMEFs to growth in the environments that were growth restrictive for 4.1B(+/+)iMEFs and to form tumors in nude mice, whereas 4.1B(+/+)iMEFs were unable to form tumors in vivo. The histological examination revealed that the tumors generated by 4.1B(-/-) iMEFs were desmoid tumors with features of local invasion. Moreover, loss of 4.1B significantly accelerated cell cycle progression, accompanied by activation of typical proto-oncogene ERK, AKT, and the G1/S regulatory pathway (p16(INK4A)-pRb pathway), and up-regulation of many members of the Wnt gene family. In particular, 4.1B(-/-) iMEFs exhibited nuclear accumulation of -catenin, which is an indicator for desmoid tumor, with down-regulation of E-cadherin expression and up-regulation of snail, zeb1, and vimentin expression, indicating that EMT potentially occurred in transformed 4.1B(-/-) iMEFs. Moreover, we showed that 4.1B interacted with E-cadherin in MEF cells. Thus, our study provides previously unidentified roles and mechanisms of 4.1B in cellular transformation. (c) 2016 Wiley Periodicals, Inc.