Department of Hematology/Oncology, Medicine, Medical University of South Carolina, Charleston, South Carolina, USA.
Cancer Prev Res (Phila). 2011 Mar;4(3):454-62. doi: 10.1158/1940-6207.CAPR-10-0299. Epub 2011 Jan 5.
It is important to identify novel and effective targets for cancer prevention and therapy against head and neck squamous cell carcinoma (HNSCC), one of the most lethal cancers. Accumulating evidence suggests that the bioactive sphingolipids, such as sphingosine-1-phosphate (S1P) and its generating enzyme, sphingosine kinase 1 (SphK1) play pivotal roles in several important biological functions including promoting tumor growth and carcinogenesis. However, roles of SphK1/S1P in HNSCC development and/or progression have not been defined previously. Therefore, in this study, we first analyzed the expression of SphK1 in human HNSCC tumor samples and normal head & neck tissues (n = 78 and 17, respectively) using immunohistochemistry. The data showed that SphK1 is overexpressed in all of the HNSCC tumors tested (stages I-IV). We next investigated whether SphK1 is necessary for HNSCC development. To define the role of SphK1/S1P in HNSCC development, we utilized 4-nitroquinoline-1-oxide (4-NQO)-induced HNSCC model in wild-type mice compared with SphK1(-/-) knockout (KO) mice. Remarkably, we found that the genetic loss of SphK1, which reduced S1P generation, significantly prevented 4-NQO-induced HNSCC carcinogenesis, with decreased tumor incidence, multiplicity, and volume when compared with controls. Moreover, our data indicated that prevention of 4-NQO-induced HNSCC development in SphK1(-/-) KO mice might be associated with decreased cell proliferation, increased levels of cleaved (active) caspase 3, and downregulation of phospho (active) AKT expression. Thus, these novel data suggest that SphK1/S1P signaling may play important roles in HNSCC carcinogenesis, and that targeting SphK1/S1P might provide a novel strategy for chemoprevention and treatment against HNSCC.
确定新的有效靶点对于预防和治疗头颈部鳞状细胞癌（HNSCC）至关重要，HNSCC 是最致命的癌症之一。越来越多的证据表明，生物活性鞘脂，如 1-磷酸鞘氨醇（S1P）及其生成酶，鞘氨醇激酶 1（SphK1），在促进肿瘤生长和致癌作用等多种重要生物学功能中发挥关键作用。然而，SphK1/S1P 在 HNSCC 发展和/或进展中的作用以前尚未确定。因此，在这项研究中，我们首先使用免疫组织化学法分析了 78 个人类 HNSCC 肿瘤样本和 17 份正常头颈部组织中 SphK1 的表达。数据表明，所有测试的 HNSCC 肿瘤均过度表达 SphK1。接下来，我们研究了 SphK1 是否对头颈癌的发展是必需的。为了确定 SphK1/S1P 在 HNSCC 发展中的作用，我们在野生型小鼠中利用 4-硝基喹啉-1-氧化物（4-NQO）诱导的 HNSCC 模型与 SphK1（-/-）敲除（KO）小鼠进行比较。值得注意的是，我们发现 SphK1 的遗传缺失，减少 S1P 的生成，显著地预防了 4-NQO 诱导的 HNSCC 癌变，与对照组相比，肿瘤发生率、多发性和体积均降低。此外，我们的数据表明，SphK1（-/-）KO 小鼠中 4-NQO 诱导的 HNSCC 发展的预防可能与细胞增殖减少、裂解（活性）半胱天冬酶 3 水平增加以及磷酸化（活性）AKT 表达下调有关。因此，这些新数据表明 SphK1/S1P 信号可能在 HNSCC 致癌作用中发挥重要作用，并且靶向 SphK1/S1P 可能为预防和治疗 HNSCC 提供新的策略。
