Fan Xing, Mikolaenko Irina, Elhassan Ihab, Ni Xingzhi, Wang Yunyue, Ball Douglas, Brat Daniel J, Perry Arie, Eberhart Charles G
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Cancer Res. 2004 Nov 1;64(21):7787-93. doi: 10.1158/0008-5472.CAN-04-1446.
The role of Notch signaling in tumorigenesis can vary; Notch1 acts as an oncogene in some neoplasms, and a tumor suppressor in others. Here, we show that different Notch receptors can have opposite effects in a single tumor type. Expression of truncated, constitutively active Notch1 or Notch2 in embryonal brain tumor cell lines caused antagonistic effects on tumor growth. Cell proliferation, soft agar colony formation, and xenograft growth were all promoted by Notch2 and inhibited by Notch1. We also found that Notch2 receptor transcripts are highly expressed in progenitor cell-derived brain tumors such as medulloblastomas, whereas Notch1 is scarce or undetectable. This parallels normal cerebellar development, during which Notch2 is predominantly expressed in proliferating progenitors and Notch1 in postmitotic differentiating cells. Given the oncogenic effects of Notch2, we analyzed its gene dosage in 40 embryonal brain tumors, detecting an increased copy number in 15% of cases. Notch2 gene amplification was confirmed by fluorescence in situ hybridization in one case with extremely high Notch2 mRNA levels. In addition, expression of the Notch pathway target gene Hes1 in medulloblastomas was associated with significantly shorter patient survival (P = 0.01). Finally, pharmacological inhibition of Notch signaling suppresses growth of medulloblastoma cells. Our data indicate that Notch1 and Notch2 can have opposite effects on the growth of a single tumor type, and show that Notch2 can be overexpressed after gene amplification in human tumors.
Notch信号通路在肿瘤发生过程中的作用可能各不相同；Notch1在某些肿瘤中起癌基因作用，而在另一些肿瘤中则起肿瘤抑制基因作用。在此，我们表明不同的Notch受体在单一肿瘤类型中可产生相反的作用。在胚胎脑肿瘤细胞系中表达截短的、组成型激活的Notch1或Notch2对肿瘤生长产生拮抗作用。Notch2促进细胞增殖、软琼脂集落形成和异种移植瘤生长，而Notch1则抑制这些过程。我们还发现，Notch2受体转录本在祖细胞来源的脑肿瘤如髓母细胞瘤中高表达，而Notch1则很少或检测不到。这与正常小脑发育情况相似，在此过程中，Notch2主要在增殖的祖细胞中表达，而Notch1在有丝分裂后分化细胞中表达。鉴于Notch2的致癌作用，我们分析了40例胚胎脑肿瘤中的基因剂量，发现15%的病例中拷贝数增加。通过荧光原位杂交在1例Notch2 mRNA水平极高的病例中证实了Notch2基因扩增。此外，髓母细胞瘤中Notch信号通路靶基因Hes1的表达与患者生存期显著缩短相关（P = 0.01）。最后，Notch信号通路的药理学抑制可抑制髓母细胞瘤细胞的生长。我们的数据表明，Notch1和Notch2对单一肿瘤类型的生长可产生相反的作用，并表明Notch2在人类肿瘤中基因扩增后可过度表达。
