Departments of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Proc Natl Acad Sci U S A. 2010 Feb 23;107(8):3534-9. doi: 10.1073/pnas.0901230107. Epub 2010 Feb 2.
Ectopic Myc expression plays a key role in human tumorigenesis, and Myc dose-dependent tumorigenesis has been well established in transgenic mice, but the Myc target genes that are dependent on Myc levels have not been well characterized. In this regard, we used the human P493-6 B cells, which have a preneoplastic state dependent on the Epstein-Barr viral EBNA2 protein and a neoplastic state with ectopic inducible Myc, to identify putative ectopic Myc target genes. Among the ectopic targets, JAG2 that encodes a Notch receptor ligand Jagged2, was directly induced by Myc. Inhibition of Notch signaling through RNAi targeting JAG2 or the gamma-secretase Notch inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-(S)-phenylglycine t-butyl ester (DAPT) preferentially inhibited the neoplastic state in vitro. Furthermore, P493-6 tumorigenesis was inhibited by DAPT in vivo. Ectopic expression of JAG2 did not enhance aerobic cell proliferation, but increased proliferation of hypoxic cells in vitro and significantly increased in vivo tumorigenesis. Furthermore, the expression of Jagged2 in P493-6 tumors often overlapped with regions of hypoxia. These observations suggest that Notch signaling downstream of Myc enables cells to adapt in the tumor hypoxic microenvironment.
异位 Myc 表达在人类肿瘤发生中起关键作用，Myc 剂量依赖性肿瘤发生在转基因小鼠中得到了很好的证实，但依赖 Myc 水平的 Myc 靶基因尚未得到很好的描述。在这方面，我们使用了具有依赖 EBVNA2 蛋白的癌前状态和具有异位诱导 Myc 的肿瘤状态的人 P493-6 B 细胞，以鉴定潜在的异位 Myc 靶基因。在异位靶基因中，编码 Notch 受体配体 Jagged2 的 JAG2 被 Myc 直接诱导。通过靶向 JAG2 的 RNAi 或 Notch 抑制剂 N-[N-(3,5-二氟苯乙酰基)-L-丙氨酰]-(S)-苯丙氨酸叔丁酯（DAPT）抑制 Notch 信号，优先抑制体外的肿瘤状态。此外，DAPT 在体内抑制 P493-6 肿瘤发生。JAG2 的异位表达不会增强有氧细胞增殖，但增加了体外缺氧细胞的增殖，并显著增加了体内肿瘤发生。此外，P493-6 肿瘤中 Jagged2 的表达常常与缺氧区域重叠。这些观察结果表明，Myc 下游的 Notch 信号使细胞能够适应肿瘤缺氧微环境。
