Cytokinesis failure due to derailed integrin traffic induces aneuploidy and oncogenic transformation in vitro and in vivo.
Cytokinesis failure due to derailed integrin traffic induces aneuploidy and oncogenic transformation in vitro and in vivo.
复制标题
DOI：
10.1038/onc.2011.527
复制
发表时间：
2012-08-02
期刊：
影响因子：
8
通讯作者：
Ivaska, J.
中科院分区：
文献类型：
--
作者：
Hognas, G.;Tuomi, S.;Veltel, S.;Mattila, E.;Murumagi, A.;Edgren, H.;Kallioniemi, O.;Ivaska, J.
非整倍性在实体瘤中经常被检测到，但调节非整倍性产生的机制及其与癌症发生的相关性仍然存在争议，并且特征不完全。整合素运输的空间和时间调节对于细胞迁移和胞质分裂至关重要。由于 Rab21 小 GTP 酶的缺失或整合素 β 亚基胞质尾部的突变，整合素内吞作用受损，会导致体外胞质分裂失败。在这里，我们描述了由于交通受损而反复失败的胞质分裂足以触发非整倍体细胞的产生，这些细胞在体外表现出致癌转化的特征，并且在体内具有致瘤性。此外，在体内小鼠异种移植模型中，整合素运输受损的非转化细胞形成潜伏期较长的肿瘤。对这些肿瘤的更详细研究表明，肿瘤细胞是非整倍体。因此，异常的整联蛋白运输也与体内非整倍性和细胞转化的产生有关。在人类前列腺癌和卵巢癌样本中，Rab21 的下调与恶性肿瘤的增加相关。功能丧失实验表明，Rab21 的长期缺失足以诱导正常人上皮细胞的染色体数目畸变。这些数据首次证明整合素运输受损足以在体外和体内诱导非转化细胞转化为致瘤细胞。
Aneuploidy is frequently detected in solid tumors but the mechanisms regulating the generation of aneuploidy and their relevance in cancer initiation remain under debate and are incompletely characterized. Spatial and temporal regulation of integrin traffic is critical for cell migration and cytokinesis. Impaired integrin endocytosis, because of the loss of Rab21 small GTPase or mutations in the integrin β-subunit cytoplasmic tail, induces failure of cytokinesis in vitro. Here, we describe that repeatedly failed cytokinesis, because of impaired traffic, is sufficient to trigger the generation of aneuploid cells, which display characteristics of oncogenic transformation in vitro and are tumorigenic in vivo. Furthermore, in an in vivo mouse xenograft model, non-transformed cells with impaired integrin traffic formed tumors with a long latency. More detailed investigation of these tumors revealed that the tumor cells were aneuploid. Therefore, abnormal integrin traffic was linked with generation of aneuploidy and cell transformation also in vivo. In human prostate and ovarian cancer samples, downregulation of Rab21 correlates with increased malignancy. Loss-of-function experiments demonstrate that long-term depletion of Rab21 is sufficient to induce chromosome number aberrations in normal human epithelial cells. These data are the first to demonstrate that impaired integrin traffic is sufficient to induce conversion of non-transformed cells to tumorigenic cells in vitro and in vivo.
登录
查看更多内容
DOI：
10.1038/nrm2718
发表时间：
2009-07
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1083/jcb.200706015
发表时间：
2007-10-22
期刊：
The Journal of cell biology
影响因子：
--
作者：
Jeganathan K;Malureanu L;Baker DJ;Abraham SC;van Deursen JM
通讯作者：
van Deursen JM
DOI：
10.1083/jcb.200209016
发表时间：
2003-02-17
期刊：
The Journal of cell biology
影响因子：
--
作者：
Evans RD;Perkins VC;Henry A;Stephens PE;Robinson MK;Watt FM
通讯作者：
Watt FM
影响因子：
10.5
作者：
FASSLER, R;MEYER, M
通讯作者：
MEYER, M
影响因子：
11.2
作者：
Iwanaga, Yoichi;Chi, Ya-Hui;Jeang, Kuan-Teh
通讯作者：
Jeang, Kuan-Teh