2012年8月30日 讯 /生物谷BIOON/ --缺氧推动恶性肿瘤的进程部分是通过促进致癌转录因子HIF-1α在肿瘤细胞中的积累。肿瘤恶化也涉及肿瘤干细胞相关的膜蛋白CD24表达的增高，CD24已被证实与实验模型中肿瘤的形成和转移密切相关。
刊登在Cancer Research杂志上一则新研究中，研究人员将这两个因子联系在一起，缺氧通过CD24启动子区域的功能性缺氧反应元件（HRE）诱导CD24的表达。在常氧条件下，HIF-1α的过度表达可诱导CD24 mRNA和蛋白水平的表达，内源性HIF-1α聚聚到CD24启动子区域的追踪研究已经证实了这一点。
在体外和体内实验中，shRNA技术使得HIF-1α或CD24表达的减少导致原发性和转移性肿瘤的生长都受到抑制。HIF-1α剔除的癌细胞过表达CD24后，肿瘤细胞生长得到恢复。而CD24剔除的肿瘤细胞过表达HIF-1α后，肿瘤细胞的生长依然受到抑制。临床肿瘤样本的分析显示HIF-1α和CD24表达水平之间存在相关性，并且两者的表达均有病人生存降相关。研究结果证实了在癌症发生发展机制中两个非常重要的分子之间存在联系，CD24作为HIF-1α转录调控蛋白和生物效应分子提示CD24可作为癌症治疗一大靶点。（生物谷：Bioon.com）
doi:10.1158/0008-5472.CAN-11-3666
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CD24 is an effector of HIF-1 driven primary tumor growth and metastasis
Shibu Thomas1, Michael Harding1, Steven C Smith2, Jonathan B Overdevest3, Matthew D. Nitz3, Henry F Frierson Jr4, et al.
Hypoxia drives malignant progression in part by promoting accumulation of the oncogenic transcription factor HIF-1α in tumor cells. Tumor aggressiveness also relates to elevation of the cancer stem cell-associated membrane protein CD24, which has been causally implicated in tumor formation and metastasis in experimental models. Here we link these two elements by showing that hypoxia induces CD24 expression through a functional hypoxia responsive element (HRE) in the CD24 promoter. HIF-1α overexpression induced CD24 mRNA and protein under normoxic conditions, with this effect traced to a recruitment of endogenous HIF-1α to the CD24 promoter. shRNA mediated-attenuation of HIF-1α or CD24 expression reduced cancer cell survival in vitro and in vivo at the levels of primary and metastatic tumor growth. CD24 overexpression in HIF-1α-depleted cancer cells rescued this decrease while HIF-1α overexpression in CD24-depleted cells did not. Analysis of clinical tumor specimens revealed a correlation between HIF-1α and CD24 levels and an association of their co-expression to decreased patient survival. Our results establish a mechanistic linkage between two critically important molecules in cancer, identifying CD24 as a critical HIF-1α transcriptional target and biological effector, strengthening the rationale to target CD24 for cancer therapy.
