Goel Hira Lal, Gritsko Tatiana, Pursell Bryan, Chang Cheng, Shultz Leonard D, Greiner Dale L, Norum Jens Henrik, Toftgard Rune, Shaw Leslie M, Mercurio Arthur M
Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
The Jackson Laboratory, Bar Harbor, ME 04609, USA.
Cell Rep. 2014 May 8;7(3):747-61. doi: 10.1016/j.celrep.2014.03.059. Epub 2014 Apr 24.
Although the α6β1 integrin has been implicated in the function of breast and other cancer stem cells (CSCs), little is known about its regulation and relationship to mechanisms involved in the genesis of CSCs. We report that a CD44(high)/CD24(low) population, enriched for CSCs, is comprised of distinct epithelial and mesenchymal populations that differ in expression of the two α6 cytoplasmic domain splice variants: α6A and α6B. α6Bβ1 expression defines the mesenchymal population and is necessary for CSC function, a function that cannot be executed by α6A integrins. The generation of α6Bβ1 is tightly controlled and occurs as a consequence of an autocrine vascular endothelial growth factor (VEGF) signaling that culminates in the transcriptional repression of a key RNA-splicing factor. These data alter our understanding of how α6β1 contributes to breast cancer, and they resolve ambiguities regarding the use of total α6 (CD49f) expression as a biomarker for CSCs.
尽管α6β1整合素与乳腺及其他癌症干细胞（CSC）的功能有关，但其调控以及与CSC发生机制的关系却鲜为人知。我们报告称，富含CSC的CD44(高)/CD24(低)群体由不同的上皮和间充质群体组成，这两个群体在α6细胞质结构域的两种剪接变体α6A和α6B的表达上存在差异。α6Bβ1的表达定义了间充质群体，并且是CSC功能所必需的，而α6A整合素无法执行该功能。α6Bβ1的产生受到严格控制，是自分泌血管内皮生长因子（VEGF）信号传导的结果，该信号传导最终导致关键RNA剪接因子的转录抑制。这些数据改变了我们对α6β1如何促成乳腺癌的理解，并且解决了关于将总α6（CD49f）表达用作CSC生物标志物的模糊问题。
