大肠腺瘤和腺癌组织中缺氧诱导因子-1α的表达及其与VEGF、微血管密度的关系

背景与目的:缺氧诱导因子-1α(hypoxia-inducible factor 1 alpha,HIF-1α)是肿瘤细胞适应缺氧而产生的一种核转录因子,在促进肿瘤新生血管生成中起重要作用。本研究旨在探讨大肠腺瘤和腺癌组织中HIF-1α的表达及其与血管内皮生长因子(vascular endothelial growth factor,VEGF)、微血管密度(microvessel density,MVD)的关系。方法:采用原位杂交技术检测HIF-1α mRNA,应用免疫组织化学方法检测VEGF蛋白的表达,用CD34单克隆抗体标记血管内皮细胞并计数MVD。结果:大肠腺癌组织HIF-1α mRNA阳性表达率为67.8％(42/62),腺瘤组织为44.4％(8/18)。腺癌组织从Dukes’A期到Dukes’C+D期HIF-lα mRNA表达阳性率不断增加(P<0.05)。HIF-1α mRNA表达平均阳性率为:腺瘤44.4％;腺癌Dukes’A期41.2％,Dukes’B期72.2％,Dukes’C+D期81.5％。腺癌组VEGF阳性表达率高于腺瘤组(59.7％ vs 33.3％,P<0.005).HIF-1α表达与VEGF呈正相关(r_s=0.768,P<0.01),与MVD呈正相关(r_s=0.683,P<0.05)。结论:HIF-1α及其靶基因 VEGF的过度表达与肿瘤新生血管形成呈正相关,这在大肠腺瘤癌变及大肠腺癌发展过程中可能起重要作用。

Relationship of hypoxia-inducible factor 1 alpha (HIF-1alpha) gene expression with vascular endothelial growth factor (VEGF) and microvessel density (MVD) in human colorectal adenoma and adenocarcinoma

BACKGROUND & OBJECTIVE: Hypoxia-inducible factor-1 alpha (HIF-1alpha), a transcriptional factor response to hypoxia plays an important role in tumor angiogenesis. This study was designed to examine the expression of HIF-1alpha gene and its relationship with vascular endothelial growth factor (VEGF) protein and microvessel density (MVD). METHODS: HIF-1alpha gene expression was analyzed using in situ hybridization, and VEGF expression levels were determined by immunohistochemistry in colorectal adenomas and primary colorectal adenocarcinomas. Microvessel density (MVD) was determined by anti-CD34 immunostaining. RESULTS: Positive expression of HIF-1alpha mRNA were found in 67.8% (42/62) of the colorectal adenocarcinomas and 44.4% (8/18) of the adenomas. The mean percentage of HIF-1alpha mRNA positive cells increased gradually with the development from Dukes'stage A to stage C+D (P< 0.05). The frequencies of HIF-1alpha positive cells in pathologic stage of the specimens were as follows: adenoma 8%, Dukes A 14%, Dukes B 23%, Dukes C+D 35%. The positive expression rate of VEGF protein in colorectal adenocarcinoma group was significantly higher than that in colorectal adenoma group (59.7% vs 33.3%,P< 0.05). During colorectal tumor progression, the expression of HIF-1alphamRNA was positively correlated with the VEGF protein expression and MVD (r(s) = 0.768 P< 0.01 and r(s) = 0.683 P< 0.05, respectively). CONCLUSION: These results suggest that tumor angiogenesis induced by HIF-1alpha mRNA and VEGF protein might play an important role in tumorigenesis of colorectal adenoma and progression of colorectal cancer.