Aberrant expression of the transcription factors snail and slug alters the response to genotoxic stress
Aberrant expression of the transcription factors snail and slug alters the response to genotoxic stress
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DOI：
10.1128/mcb.24.17.7559-7566.2004
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发表时间：
2004-09-01
影响因子：
5.3
通讯作者：
Wade, PA
中科院分区：
文献类型：
--
作者：
Kajita, M;McClinic, KN;Wade, PA
Snail和Slug是在后生动物发育过程中参与胚胎模式形成的密切相关的转录抑制因子。在人类癌症中，Snail和/或Slug的异常表达与侵袭性生长潜力相关，这一特性主要归因于它们直接抑制其产物参与细胞-细胞粘附的基因（如E-钙粘蛋白、闭合蛋白和密蛋白）转录的能力。为了研究Snail或Slug异常表达介导的上皮细胞命运改变的分子机制，我们分析了这些因子在人类癌细胞中外源性表达的后果。Snail或Slug的异常表达导致细胞形态的变化、正常细胞-细胞接触的丧失以及侵入性生长特性的获得。Snail或Slug表达也促进了对DNA损伤引起的程序性细胞死亡的抵抗。详细的分子分析揭示了直接转录抑制的多种因素，充分记录的作用，在程序性细胞死亡。通过RNA干扰消除内源性Snail导致对DNA损伤的敏感性增加，伴随着被鉴定为Snail靶点的促凋亡因子的表达增加。因此，Snail或Slug的异常表达可通过增加对程序性细胞死亡的抗性来促进肿瘤发生。
Snail and Slug are closely related transcriptional repressors involved in embryonic patterning during metazoan development. In human cancer, aberrant expression of Snail and/or Slug has been correlated with invasive growth potential, a property primarily attributed to their ability to directly repress transcription of genes whose products are involved in cell-cell adhesion, such as E-cadherin, occludin, and claudins. To investigate the molecular mechanisms of alterations in epithelial cell fate mediated by aberrant expression of Snail or Slug, we analyzed the consequences of exogenous expression of these factors in human cancer cells. Aberrant expression of either Snail or Slug led to changes in cell morphology, the loss of normal cell-cell contacts, and the acquisition of invasive growth properties. Snail or Slug expression also promoted resistance to programmed cell death elicited by DNA damage. Detailed molecular analysis revealed direct transcriptional repression of multiple factors with well-documented roles in programmed cell death. Depletion of endogenous Snail by RNA interference led to increased sensitivity to DNA damage accompanied by increased expression of the proapoptotic factors identified as targets of Snail. Thus, aberrant expression of Snail or Slug may promote tumorigenesis through increased resistance to programmed cell death.