期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2014408118
关键词
circulating tumor cells (CTCs); breast cancer; metastasis; desmoglein2 (DSG2); HIF1 alpha
资金
- Academia Sinica [AS-SUMMIT-108, AS-SUMMIT-109]
- Taiwan Ministry of Science and Technology [MOST 109-0210-01-18-02, MOST 108-3114-Y-001002, MOST 107-0210-01-19-01, MOST 105-2628-B-001-008-MY3, MOST108-2311-B-001-005-MY3]
High expression of DSG2 promotes tumor growth, increases the prevalence of CTC clusters, and facilitates distant organ colonization. The dynamic regulation of DSG2 by hypoxia, with down-regulation in hypoxic regions of primary tumors leading to elevated EMT gene expression, allows cells to detach from the primary tumor and undergo intravasation. The derepression of DSG2 after intravasation and release of hypoxic stress is associated with increased ability to colonize distant organs, mediated by Hypoxia-Induced Factor1 alpha (HIF1 alpha).
Metastasis is the major cause of cancer death. An increased level of circulating tumor cells (CTCs), metastatic cancer cells that have intravasated into the circulatory system, is particularly associated with colonization of distant organs and poor prognosis. However, the key factors required for tumor cell dissemination and colonization remain elusive. We found that high expression of desmoglein2 (DSG2), a component of desmosome-mediated intercellular adhesion complexes, promoted tumor growth, increased the prevalence of CTC clusters, and facilitated distant organ colonization. The dynamic regulation of DSG2 by hypoxia was key to this process, as down-regulation of DSG2 in hypoxic regions of primary tumors led to elevated epithelial-mesenchymal transition (EMT) gene expression, allowing cells to detach from the primary tumor and undergo intravasation. Subsequent derepression of DSG2 after intravasation and release of hypoxic stress was associated with an increased ability to colonize distant organs. This dynamic regulation of DSG2 was mediated by Hypoxia-Induced Factor1 alpha (HIF1 alpha). In contrast to its more widely observed function to promote expression of hypoxia-inducible genes, HIF1 alpha repressed DSG2 by recruitment of the polycomb repressive complex 2 components, EZH2 and SUZ12, to the DSG2 promoter in hypoxic cells. Consistent with our experimental data, DSG2 expression level correlated with poor prognosis and recurrence risk in breast cancer patients. Together, these results demonstrated the importance of DSG2 expression in metastasis and revealed a mechanism by which hypoxia drives metastasis.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据