Genetic Identification of SEMA3F as an Antilymphangiogenic Metastasis Suppressor Gene in Head and Neck Squamous Carcinoma.
Genetic Identification of SEMA3F as an Antilymphangiogenic Metastasis Suppressor Gene in Head and Neck Squamous Carcinoma.
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DOI：
10.1158/0008-5472.can-14-3121
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发表时间：
2015-07-15
期刊：
影响因子：
11.2
通讯作者：
Gutkind JS
中科院分区：
文献类型：
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作者：
Doçi CL;Mikelis CM;Lionakis MS;Molinolo AA;Gutkind JS
头颈鳞状细胞癌（HNSCC）经常转移至局部淋巴结，淋巴结受累是临床预后不良的最重要的预后因素之一。 HNSCC 具有显着的淋巴管生成性，是利用淋巴管系统进行恶性传播的癌症的明显例子；然而，HNSCC 淋巴管生成的分子机制仍知之甚少。有趣的是，我们发现轴突引导分子 Semaphorin 3F (SEMA3F) 是 HNSCC 中前 1% 表达不足的基因之一，SEMA3F 的基因组缺失与转移增加和生存率降低相关。 SEMA3F 作用于其共受体、丛蛋白和神经毡蛋白，其中神经毡蛋白-2 (NRP2) 在淋巴内皮细胞 (LEC) 中高表达，但在口腔上皮和大多数 HNSCC 中不表达。我们发现重组SEMA3F可促进LEC塌陷并有效抑制体内淋巴管生成。通过重建所有可能的丛蛋白和神经毡蛋白组合，我们发现SEMA3F通过多种受体发挥作用，但主要需要NRP2在LEC中发出信号。使用原位 HNSCC 转移小鼠模型，我们提供了 SEMA3F 重新表达减少淋巴管生成和淋巴结转移的直接证据。此外，对大量组织的分析表明，SEMA3F 在 HNSCC 进展过程中逐渐丢失，同时肿瘤淋巴管生成增加。 SEMA3F 定位于 3p21，这是 HNSCC 和许多其他常见人类恶性肿瘤中早期且经常被删除的位点。因此，SEMA3F可能代表一种在癌症进展过程中广泛丢失的抗淋巴管生成转移抑制基因，因此可作为预后生物标志物和阻止转移的治疗干预的有吸引力的靶点。
Head and neck squamous cell carcinomas (HNSCC) often metastasize to locoregional lymph nodes, and lymph node involvement represents one of the most important prognostic factors of poor clinical outcome. HNSCC are remarkably lymphangiogenic and represent a clear example of a cancer that utilizes the lymphatic vasculature for malignant dissemination; however, the molecular mechanisms underlying lymphangiogenesis in HNSCC is still poorly understood. Of interest, we found that an axon guidance molecule, Semaphorin 3F (SEMA3F), is among the top 1% underexpressed genes in HNSCC, and that genomic loss of SEMA3F correlates with increased metastasis and decreased survival. SEMA3F acts on its co-receptors, plexins and neuropilins, among which neuropilin-2 (NRP2) is highly expressed in lymphatic endothelial cells (LECs) but not in oral epithelium and most HNSCCs. We show that recombinant SEMA3F promotes LEC collapse and potently inhibits lymphangiogenesis in vivo. By reconstituting all possible plexin and neuropilin combinations, we found that SEMA3F acts through multiple receptors, but predominantly requires NRP2 to signal in LECs. Using orthotopic HNSCC metastasis mouse models, we provide direct evidence that SEMA3F re-expression diminishes lymphangiogenesis and lymph node metastasis. Furthermore, analysis of a large tissue collection revealed that SEMA3F is progressively lost during HNSCC progression, concomitant with increased tumor lymphangiogenesis. SEMA3F is localized to 3p21, an early and frequently deleted locus in HNSCC and many other prevalent human malignancies. Thus, SEMA3F may represent an antilymphangiogenic metastasis suppressor gene widely lost during cancer progression, hence serving as a prognostic biomarker and an attractive target for therapeutic intervention to halt metastasis.