Snail and Slug Mediate Radioresistance and Chemoresistance by Antagonizing p53-Mediated Apoptosis and Acquiring a Stem-Like Phenotype in Ovarian Cancer Cells
Snail and Slug Mediate Radioresistance and Chemoresistance by Antagonizing p53-Mediated Apoptosis and Acquiring a Stem-Like Phenotype in Ovarian Cancer Cells
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DOI：
10.1002/stem.154
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发表时间：
2009-01-01
期刊：
影响因子：
5.2
通讯作者：
Bapat, Sharmila A.
中科院分区：
文献类型：
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作者：
Kurrey, Nawneet K.;Jalgaonkar, Swati P.;Bapat, Sharmila A.
转录抑制因子Snail和Slug通过介导上皮-间充质转化(EMT)促进肿瘤的进展，从而导致肿瘤细胞的侵袭和转移。我们扩展这一目前的理解，以证明他们参与了辐射和紫杉醇抵抗的发展。这一过程是通过获得在应激条件下被抑制的一组新的基因靶点来协调的，有效地灭活了P53介导的细胞凋亡，而另一组靶点继续介导EMT。抑制活动与特定基因的同时解除抑制作用相辅相成，从而获得干细胞样特征。这些细胞被赋予三个关键能力，即EMT，对P53介导的凋亡的抵抗，以及自我更新计划，这些共同决定了转移性癌症干细胞的功能和生存。EMT提供了一种逃逸到新的、不那么不利的利基环境的机制；对凋亡的抵抗确保了细胞在原发肿瘤的应激条件下存活；而获得“干性”确保了产生微转移到大转移所需的临界肿瘤质量。我们的发现，除了实现直接基因靶点的相当大的扩展外，更重要的是证明，这种由蜗牛和鼻涕虫介导的优雅的基因调控协同调节对于癌细胞获得干细胞特性以抵抗放疗或化疗介导的细胞压力至关重要，这可能是侵袭性癌症转移的一个决定性因素。
The transcriptional repressors Snail and Slug contribute to cancer progression by mediating epithelial-mesenchymal transition (EMT), which results in tumor cell invasion and metastases. We extend this current understanding to demonstrate their involvement in the development of resistance to radiation and paclitaxel. The process is orchestrated through the acquisition of a novel subset of gene targets that is repressed under conditions of stress, effectively inactivating p53-mediated apoptosis, while another subset of targets continues to mediate EMT. Repressive activities are complemented by a concurrent derepression of specific genes resulting in the acquisition of stem cell-like characteristics. Such cells are bestowed with three critical capabilities, namely EMT, resistance to p53-mediated apoptosis, and a self-renewal program, that together define the functionality and survival of metastatic cancer stem cells. EMT provides a mechanism of escape to a new, less adverse niche; resistance to apoptosis ensures cell survival in conditions of stress in the primary tumor; whereas acquisition of "stemness'' ensures generation of the critical tumor mass required for progression of micrometastases to macrometastases. Our findings, besides achieving considerable expansion of the inventory of direct genes targets, more importantly demonstrate that such elegant cooperative modulation of gene regulation mediated by Snail and Slug is critical for a cancer cell to acquire stem cell characteristics toward resisting radiotherapy- or chemotherapy-mediated cellular stress, and this may be a determinative aspect of aggressive cancer metastases. STEM CELLS 2009; 27: 2059-2068