Laboratory of Experimental Oncology, CRS Development of Biomolecular Therapies, SSN Emilia Romagna Istituti Ortopedici Rizzoli IRCCS, Bologna, Italy.
J Clin Invest. 2010 Mar;120(3):668-80. doi: 10.1172/JCI36667. Epub 2010 Feb 8.
Ewing sarcoma (EWS) is an aggressive bone tumor of uncertain cellular origin. CD99 is a membrane protein that is expressed in most cases of EWS, although its function in the disease is unknown. Here we have shown that endogenous CD99 expression modulates EWS tumor differentiation and malignancy. We determined that knocking down CD99 expression in human EWS cell lines reduced their ability to form tumors and bone metastases when xenografted into immunodeficient mice and diminished their tumorigenic characteristics in vitro. Further, reduction of CD99 expression resulted in neurite outgrowth and increased expression of beta-III tubulin and markers of neural differentiation. Analysis of a panel of human EWS cells revealed an inverse correlation between CD99 and H-neurofilament expression, as well as an inverse correlation between neural differentiation and oncogenic transformation. As knockdown of CD99 also led to an increase in phosphorylation of ERK1/2, we suggest that the CD99-mediated prevention of neural differentiation of EWS occurs through MAPK pathway modulation. Together, these data indicate a new role for CD99 in preventing neural differentiation of EWS cells and suggest that blockade of CD99 or its downstream molecular pathway may be a new therapeutic approach for EWS.
尤文肉瘤（EWS）是一种起源不明的侵袭性骨肿瘤。CD99 是一种膜蛋白，在大多数 EWS 病例中都有表达，但其在疾病中的功能尚不清楚。在这里，我们已经表明，内源性 CD99 表达调节 EWS 肿瘤分化和恶性程度。我们确定，在异种移植到免疫缺陷小鼠中时，敲低人 EWS 细胞系中的 CD99 表达会降低其形成肿瘤和骨转移的能力，并降低其体外致瘤特性。此外，降低 CD99 表达会导致轴突生长和β-III 微管蛋白以及神经分化标志物的表达增加。对一系列人 EWS 细胞的分析表明，CD99 与 H-神经丝表达之间存在负相关，以及神经分化与致癌转化之间存在负相关。由于敲低 CD99 也导致 ERK1/2 的磷酸化增加，因此我们推测 CD99 介导的 EWS 细胞神经分化的预防是通过 MAPK 途径调节发生的。总之，这些数据表明 CD99 在防止 EWS 细胞神经分化中具有新的作用，并表明阻断 CD99 或其下游分子途径可能是 EWS 的一种新的治疗方法。
