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

缺氧诱导因子-1(HIF-1)是一种氧调节的转录激活因子，在维持氧稳态中起重要作用。我们检测了39例舌鳞癌活检标本中的HIF-1a蛋白、血管形成和P53蛋白，其中12例(31%)HIF-1a蛋白阳性。HIF-1a的表达与癌细胞颈淋巴转移和远处器官转移密切相关。HIF-1a阳性肿瘤新生血管比例高，血管数量多，管径小。突变型P53(mt-p53)的表达与HIF-1a的表达无明显相关性，但mt-p53/HIF-1a阳性的病例与转移密切相关，且累积总生存期较短。这些结果表明，HIF-1a的表达结合P53的状态可能是舌癌新生血管形成的指标，可作为舌癌转移的新的预测和预后指标。DNA芯片分析显示，包括几个与HIF-1、Pim-1和肾上腺髓质素相关的候选基因。PIM-1被证明与myc协同抑制细胞凋亡，并诱导血细胞肿瘤的发生。我们检测了Pim-1在舌鳞状细胞癌中的表达，发现约40%的肿瘤中表达HIF-1a和Pim-1，并证实了Pim-1的增殖能力与远处转移密切相关。在约40%的口腔癌中发现肾上腺髓质素，并显示有新生血管的高转移潜能。

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.