2012年8月30日 訊 /生物谷BIOON/ --缺氧推動惡性腫瘤的進程部分是通過促進致癌轉(zhuǎn)錄因子HIF-1α在腫瘤細胞中的積累,。腫瘤惡化也涉及腫瘤干細胞相關(guān)的膜蛋白CD24表達的增高，CD24已被證實與實驗?zāi)Ｐ椭心[瘤的形成和轉(zhuǎn)移密切相關(guān),。
刊登在Cancer Research雜志上一則新研究中,，研究人員將這兩個因子聯(lián)系在一起，缺氧通過CD24啟動子區(qū)域的功能性缺氧反應(yīng)元件（HRE）誘導(dǎo)CD24的表達,。在常氧條件下,，HIF-1α的過度表達可誘導(dǎo)CD24 mRNA和蛋白水平的表達，內(nèi)源性HIF-1α聚聚到CD24啟動子區(qū)域的追蹤研究已經(jīng)證實了這一點,。
在體外和體內(nèi)實驗中,，shRNA技術(shù)使得HIF-1α或CD24表達的減少導(dǎo)致原發(fā)性和轉(zhuǎn)移性腫瘤的生長都受到抑制。HIF-1α剔除的癌細胞過表達CD24后,，腫瘤細胞生長得到恢復(fù),。而CD24剔除的腫瘤細胞過表達HIF-1α后，腫瘤細胞的生長依然受到抑制,。臨床腫瘤樣本的分析顯示HIF-1α和CD24表達水平之間存在相關(guān)性,，并且兩者的表達均有病人生存降相關(guān)。研究結(jié)果證實了在癌癥發(fā)生發(fā)展機制中兩個非常重要的分子之間存在聯(lián)系,，CD24作為HIF-1α轉(zhuǎn)錄調(diào)控蛋白和生物效應(yīng)分子提示CD24可作為癌癥治療一大靶點,。（生物谷：Bioon.com）
doi:10.1158/0008-5472.CAN-11-3666
PMC:
PMID:
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.
