Smith Steven C, Oxford Gary, Wu Zhong, Nitz Matthew D, Conaway Mark, Frierson Henry F, Hampton Garret, Theodorescu Dan
Department of Molecular Physiology, University of Virginia, Charlottesville, Virginia, USA.
Cancer Res. 2006 Feb 15;66(4):1917-22. doi: 10.1158/0008-5472.CAN-05-3855.
Ral GTPases are important mediators of transformation, tumorigenesis, and cancer progression. We recently identified the metastasis-associated protein CD24, a glycosyl phosphatidyl inositol-linked surface protein, as a downstream target of Ral signaling by profiling the expression of RalA/B-depleted bladder carcinoma cells. Because CD24 is highly expressed in bladder and many other tumor types, we sought to determine if this protein plays an essential role in maintaining the malignant phenotype. Here, we show that loss of CD24 function in cell lines derived from common tumor types is associated with decreased rates of cell proliferation, clonogenicity in soft agar, changes in the actin cytoskeleton, and induction of apoptosis. Given these phenotypes, we evaluated a human bladder cancer tissue microarray by immunohistochemistry for CD24 to determine if CD24 is a prognostic cancer biomarker. Multivariate analysis showed that increased CD24 expression correlated with shorter patient disease-free survival (P = 0.07). In conclusion, we show that CD24 is a novel and functionally relevant Ral-regulated target and a potentially important prognostic marker. We suggest that these insights may lead to future therapeutic approaches that seek to eliminate CD24 function in cancer cells.
Ral GTP酶是细胞转化、肿瘤发生和癌症进展的重要介导因子。我们最近通过分析RalA/B缺失的膀胱癌细胞的表达情况，确定转移相关蛋白CD24（一种糖基磷脂酰肌醇连接的表面蛋白）是Ral信号传导的下游靶点。由于CD24在膀胱及许多其他肿瘤类型中高表达，我们试图确定该蛋白在维持恶性表型中是否起关键作用。在此，我们表明，源自常见肿瘤类型的细胞系中CD24功能缺失与细胞增殖率降低、软琼脂克隆形成能力下降、肌动蛋白细胞骨架变化及凋亡诱导有关。鉴于这些表型，我们通过免疫组织化学评估了人膀胱癌组织芯片中CD24的表达，以确定CD24是否为癌症预后生物标志物。多变量分析显示，CD24表达增加与患者无病生存期缩短相关（P = 0.07）。总之，我们表明CD24是一种新型且功能相关的Ral调控靶点以及潜在的重要预后标志物。我们认为这些见解可能会带来未来旨在消除癌细胞中CD24功能的治疗方法。
