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

Relationship of Hypoxia-lnducible Factor 1 Alpha (HIF-1α) Gene Expression with Vascular Endothelial Growth Factor (VEGF) and Microvessel Density (MVD) in Human Colorectal Adenoma and Adenocarcinoma

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。

BACKGROUND & OBJECTIVE: Hypoxia-inducibie factor-1 alpha (HIF-1α), a transcriptional factor response to hypoxia plays an important role in tumor angiogenesis. This study was designed to examine the expression of HIF-1α gene and its relationship with vascular endothelial growth factor (VEGF) protein and microvessel density (MVD). METHODS: HIF-1α 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-1α 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-1α mRNA positive cells increased gradually with the development from Dukes'stage A to stage C + D ( P <0.05) . The frequencies of HIF-1?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-1αmRNA was positively correlated with the VEGF protein expression and MVD ( rs = 0.768 P < 0.01 and rs = 0.683 P<0.05, respectively). CONCLUSION: These results suggest that tumor angiogenesis induced by HlF-1α mRNA and VEGF protein might play an important role in tumorigenesis of colorectal adenoma and progression of colorectal cancer.