Identification of HIF-1a target genes and their biological roles in oral carcinoma.

缺氧诱导因子1（Hypoxia-inducible factor 1, HIF-1）是一种受氧调控的转录激活因子，在维持氧稳态中起重要作用。我们在39例舌鳞状细胞癌患者的活检标本中检测了HIF-1a蛋白、血管化和p53蛋白，39例中有12例（31%）检测到HIF-1a。观察到HIF-1a表达与癌细胞转移到颈部淋巴结和远处器官之间存在显著相关性。hif -1a阳性肿瘤新生血管比例高，血管数量多，血管直径小。突变型p53（mt-p53）表达与HIF-1a表达无显著相关性，然而，mt-p53/HIF-1a阳性病例与转移高度相关，并表现出较短的累积总生存期。这些结果表明，HIF-1a的表达与p53状态的结合可能是舌鳞状细胞癌新血管形成的一个指标，可能成为舌鳞状细胞癌转移的一个新的预测和预后参数。DNA微阵列分析显示，有几个候选基因对HIF-1、pim-1和肾上腺髓质素有反应。Pim-1与myc协同抑制细胞凋亡，诱导血细胞发生肿瘤。我们在舌鳞癌中检测了皮姆-1，发现皮姆-1在约40%的肿瘤中检测到HIF-1a和皮姆-1的相关表达，并确定了增殖潜能与远处转移的密切关系。肾上腺髓质素在约40%的口腔癌中被发现，并显示出高转移潜力和新血管形成。

Hypoxia-inducible factor 1(HIF-1) is an oxygen-regulated transcriptional activator that plays an essential role in the maintenance of oxygen homeostasis. We examined HIF-1a protein, vascularization and p53 protein in 39 biopsy specimens from tongue SCC patients HIF-1a was identified in 12 of 39 (31%) cases examined. A significant correlation was observed between HIF-1a expression and cancer cell metastasis into the cervical lymph nodes and distant organs. HIF-1a-positive tumors showed a high ratio of neovascularization with a large number and smaller diameter of blood vessels. Mutant-p53(mt-p53) expression was not significantly associated with HIF-1a expression, however, mt-p53/HIF-1a-positive cases highly correlated with metastasis, and showed significant by shorter cumulative overall survival. These results indicate that HIF-1a expression in combination with p53 status would be an indicator of neovasculanzation, which could be a new predictive and prognostic parameter for metastasis in tongue SCC.DNA microarray analysis revealed that several candidated genes responsive for HIF-1, and pim-1 and adrenomedullin were included. pim-1 was shown to inhibit apoptosis cooperating with myc and induce tumorigenesis in blood cells. We examined pim-1 in tongue squamous cell carcinomas and pim-1 was detected in about 40% tumors Correlated expression of HIF-1a and pim-1, and the close relationship between proliferative potential and distant metastasis were identified. Adrenomedullin was identified in about 40% of oral carcinoma, and high metastatic potential with neovasculization was shown.