Department of Otolaryngology - Head and Neck Surgery, University of Southern California, Keck School of Medicine, Los Angeles, California, USA.
Head Neck. 2011 Feb;33(2):178-88. doi: 10.1002/hed.21418.
Sphingosine kinase 1 (SphK1) is an important regulator of apoptosis, survival, and proliferation in cancer cells. SphK1 expression in head and neck squamous cell cancer (HNSCC) cell lines and tumor tissue was assessed, and the efficacy of SphK1 knockdown in increasing tumor radiosensitivity was evaluated in vitro and in vivo.
Expression of SphK1 was determined by immunohistochemistry, Western blot, and real-time polymerase chain reaction (RT-PCR) in 34 prospectively collected HNSCC tumor samples. HNSCC cell lines squamous cell carcinoma (SCC)-15 and SCC-25 were treated with SphK1 inhibitor SKI-II and siRNA targeting SphK1 with and without radiation, and the cell viability was assessed. SCC-15 cells with and without transfection of SphK1 siRNA were then injected into athymic nude mice to develop tumor xenografts, and these 2 groups were further divided into 1 group that received radiation and 1 group that did not. Tumor size was measured over 18 days, when the animals were killed and the tumors were evaluated by immunohistochemistry.
SphK1 is found in both HNSCC cell lines and human tumor samples, with higher expression correlated with advanced tumor stage, nodal involvement, and recurrence. In vitro, both SCC-15 and SCC-25 were found to be radioresistant; however, they were sensitized by administration of SKI-II and transfection with siRNA targeting SphK1. In vivo, SphK1-siRNA transfected xenografts were decreased in size compared with both nonradiated control and radiated control mice, whereas mice with both SphK1-siRNA and radiation treatment showed a synergistic reduction in tumor volume. Histopathologic analysis demonstrated a decreased proliferative state in SphK1-siRNA transfected tumors.
SphK1 is upregulated in HNSCC, and inhibition of SphK1 sensitizes HNSCC to radiation-induced cytotoxicity.
神经酰胺激酶 1（SphK1）是癌细胞凋亡、存活和增殖的重要调节因子。评估了 SphK1 在头颈部鳞状细胞癌（HNSCC）细胞系和肿瘤组织中的表达，并在体外和体内评估了 SphK1 敲低增加肿瘤放射敏感性的效果。
在 34 例前瞻性收集的 HNSCC 肿瘤样本中，通过免疫组织化学、Western blot 和实时聚合酶链反应（RT-PCR）检测 SphK1 的表达。用 SphK1 抑制剂 SKI-II 和 SphK1 靶向 siRNA 处理 HNSCC 细胞系鳞状细胞癌（SCC）-15 和 SCC-25，并在有无辐射的情况下评估细胞活力。然后将转染 SphK1 siRNA 的 SCC-15 细胞注入裸鼠体内以建立肿瘤异种移植物，将这 2 组进一步分为接受辐射的 1 组和未接受辐射的 1 组。在 18 天内测量肿瘤大小，处死动物后通过免疫组织化学评估肿瘤。
SphK1 存在于 HNSCC 细胞系和人类肿瘤样本中，高表达与晚期肿瘤分期、淋巴结受累和复发相关。体外，SCC-15 和 SCC-25 均具有放射抗性；然而，它们通过给予 SKI-II 和转染 SphK1 靶向 siRNA 而被敏化。体内，与未照射对照和照射对照小鼠相比，转染 SphK1 siRNA 的异种移植物的大小减小，而同时转染 SphK1 siRNA 和接受放射治疗的小鼠的肿瘤体积则协同减小。组织病理学分析表明，转染 SphK1 siRNA 的肿瘤中增殖状态降低。
SphK1 在 HNSCC 中上调，抑制 SphK1 使 HNSCC 对辐射诱导的细胞毒性敏感。
