García-Heredia José Manuel, Carnero Amancio
Instituto de Biomedicina de Sevilla, IBIS, Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Consejo Superior de Investigaciones Científicas, Seville, Spain.
Department of Vegetal Biochemistry and Molecular Biology, University of Seville, Seville, Spain.
Oncotarget. 2018 Jan 11;9(10):9219-9234. doi: 10.18632/oncotarget.24186. eCollection 2018 Feb 6.
NUMB, and its close homologue NUMBL, behave as tumor suppressor genes by regulating the Notch pathway. The downregulation of these genes in tumors is common, allowing aberrant Notch pathway activation and tumor progression. However, some known differences between NUMB and NUMBL have raised unanswered questions regarding the redundancy and/or combined regulation of the Notch pathway by these genes during the tumorigenic process. We have found that NUMB and NUMBL exhibit mutual exclusivity in human tumors, suggesting that the associated tumor suppressor role is regulated by only one of the two proteins in a specific cell, avoiding duplicate signaling and simplifying the regulatory network. We have also found differences in gene expression due to or downregulation. These differences in gene regulation extend to pathways, such as WNT or Hedgehog. In addition to these differences, the downregulation of either gene triggers a cancer stem cell-like related phenotype. These results show the importance of both genes as an intersection with different effects over cancer stem cell signaling pathways.
NUMB及其紧密同源物NUMBL通过调节Notch信号通路发挥肿瘤抑制基因的作用。这些基因在肿瘤中的下调很常见，可导致Notch信号通路异常激活和肿瘤进展。然而，NUMB和NUMBL之间一些已知的差异引发了一些未解决的问题，即在肿瘤发生过程中这些基因对Notch信号通路的冗余和/或联合调节。我们发现，NUMB和NUMBL在人类肿瘤中表现出相互排斥性，这表明相关的肿瘤抑制作用在特定细胞中仅由这两种蛋白质中的一种调节，从而避免重复信号传导并简化调节网络。我们还发现，由于基因上调或下调导致基因表达存在差异。这些基因调控的差异延伸到WNT或Hedgehog等信号通路。除了这些差异外，任一基因的下调都会触发癌症干细胞样相关表型。这些结果表明这两个基因作为与癌症干细胞信号通路具有不同影响的交叉点的重要性。
