Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908, USA.
Proc Natl Acad Sci U S A. 2012 Dec 18;109(51):E3588-96. doi: 10.1073/pnas.1113960109. Epub 2012 Sep 25.
Overexpression of CD24, a glycosyl phosphatidylinositol-linked sialoglycoprotein, is associated with poor outcome in urothelial carcinoma and contributes to experimental tumor growth and metastasis. However, the requirement for CD24 (Cd24a in mice) in tumorigenesis and spontaneous metastasis from the orthotopic site remains uncharacterized. Using N-butyl-N-(4-hydroxybutyl) nitrosamine induction of invasive and metastatic bladder cancer, we show that Cd24a-deficient male mice developed fewer bladder tumors than C57BL/6 control male mice. Evaluating only mice with evidence of primary tumors, we observed that Cd24a-deficient male mice also had fewer metastases than wild-type counterparts. In parallel observations, stratification of patients based on CD24 immunohistochemical expression in their tumors revealed that high levels of CD24 are associated with poor prognosis in males. In female patients and mice the above observations were not present. Given the significant role of CD24 in males, we sought to assess the relationship between androgen and CD24 regulation. We discovered that androgen receptor knockdown in UM-UC-3 and TCCSUP human urothelial carcinoma cell lines resulted in suppression of CD24 expression and cell proliferation. Androgen treatment also led to increased CD24 promoter activity, dependent on the presence of androgen receptor. In vivo, androgen deprivation resulted in reduced growth and CD24 expression of UM-UC-3 xenografts, and the latter was rescued by exogenous CD24 overexpression. These findings demonstrate an important role for CD24 in urothelial tumorigenesis and metastasis in male mice and indicate that CD24 is androgen regulated, providing the foundation for urothelial bladder cancer therapy with antiandrogens.
CD24 是一种糖基磷脂酰肌醇连接的唾液糖蛋白，其过度表达与尿路上皮癌的不良预后相关，并有助于实验性肿瘤的生长和转移。然而，CD24（在小鼠中为 Cd24a）在肿瘤发生和原位自发转移中的需求仍未得到阐明。我们使用 N-丁基-N-（4-羟丁基）亚硝胺诱导侵袭性和转移性膀胱癌，结果表明 Cd24a 缺陷型雄性小鼠比 C57BL/6 对照雄性小鼠发展出更少的膀胱癌。仅评估有原发性肿瘤证据的小鼠，我们观察到 Cd24a 缺陷型雄性小鼠的转移也比野生型小鼠少。在平行观察中，根据肿瘤中 CD24 免疫组织化学表达对患者进行分层，结果表明 CD24 水平高与男性预后不良相关。在女性患者和小鼠中没有观察到上述现象。鉴于 CD24 在男性中的重要作用，我们试图评估雄激素和 CD24 调节之间的关系。我们发现，在 UM-UC-3 和 TCCSUP 人尿路上皮癌细胞系中敲低雄激素受体导致 CD24 表达和细胞增殖受到抑制。雄激素处理也导致 CD24 启动子活性增加，这依赖于雄激素受体的存在。在体内，雄激素剥夺导致 UM-UC-3 异种移植物的生长和 CD24 表达减少，而外源性 CD24 过表达可挽救后者。这些发现表明 CD24 在雄性小鼠的尿路上皮肿瘤发生和转移中起重要作用，并表明 CD24 受雄激素调节，为使用抗雄激素治疗尿路上皮膀胱癌提供了基础。
