期刊
ONCOGENE
卷 31, 期 31, 页码 3597-3606出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2011.527
关键词
integrin traffic; cytokinesis; aneuploidy; cancer
资金
- ERC starting grant
- Academy of Finland
- Finnish Cancer Organizations
- Sigrid Juselius Foundation
- Turku Graduate School for Biomedical Sciences
- VTT Medical Biotechnology
- EMBO LTF
- Alexander von Humboldt foundation
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 beta-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. Oncogene (2012) 31, 3597-3606; doi:10.1038/onc.2011.527; published online 28 November 2011
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