HIF-1α在直肠癌中的表达和血管生成的关系

Expression of HIF-1α and its relationship with angiogenesis in rectal cancer

目的探讨缺氧诱导因子-1α(HIF-1α)在直肠癌中的表达和血管生成的关系及其临床意义。方法分别采用免疫组化SP法检测88例直肠癌患者肿瘤组织中HIF-1α、VEGF和CD34的表达和使用蛋白印迹法(Western blot)半定量检测21例直肠癌患者新鲜肿瘤组织和12例正常直肠黏膜组织中HIF-1α的表达；并回顾性分析临床病理学资料。结果免疫组化检测结果显示直肠癌组中HIF-1α、VEGF的阳性表达率分别为65．9％(58／88),63．6％(56／88)显著高于正常对照组的16．7％(2／12)和0％(P＜0．01)；直肠癌组中MVD平均为29．6±6．1(16～51),正常对照组为15±4．8(7～22),2组比较差异有显著性意义(P＜0．01)。HIF-1α、VEGF与CD34的表达呈显著正相关(P＜0．01)。HIF-1α、VEGF和CD34的表达与肿瘤Dukes分期、淋巴结转移、远处转移显著相关(P＜0．05),而与肿瘤的病理类型、细胞分化程度无显著相关性。本组病例5年生存率为63．6％,其中HIF-1α、VEGF表达阳性组和阴性组的5年生存率分别为41．38％ vs 80％和37．93％ vs 86．67％,2者比较差异具有非常显著性意义(P＜0．01)；Cox模型多因素分析表明,HIF-1α、VEGF可能作为临床判断预后的指标。结论本研究结果提示在肿瘤的发生、发展中的缺氧过程诱导了HIF-1α的形成,从而促进靶基因VEGF的转录,导致血管生成增多,进而促进肿瘤生长、浸润和转移；HIF-1α,VEGF可作为判断直肠癌预后的参考指标。

Objective To investigate the expression of hypoxia inducible factor-1 alpha（HIF-1α in rectal cancer and its relation with angiogenesis and clinical significance. Methods The first part of the experiment,immunohistochemical streptavidin/peroxidase （SP） was used to examine the expressions of HIF-1 α, VEGF and CD34 in 88 cases of rectal cancer. The second part of the experiment, the expressions of HIF-1α in 21cases of rectal cancer and normal tissues, were detected by western blot. Results The first part of the experiment： HIF-1α and VEGF positive cells and the level of microvessel density（MVD） were significantly increased, compared with those in the normal tissues （65.9% vs 16.7%, 63.6% vs 0%, 29.6 ± 6.1 vs 14 ± 5.8, respectively P 〈0.01）. Moreover, the expressions of HIF-1α, VEGF and CD34 seemed to be closely related with the Dukes stage, lymph node metastasis and distant metastasis, but not with the sex, age and pathologic type. And the expression of HIF-1α was positively correlated with both VEGF expression and MVD level（ P 〈0.05）. The five-year-survival rate of the HIF-1α VEGF negative groups was much better than that of the positive groups （80% vs 41.38%, 86.67% vs 37.93% P 〈0.01）. The second part of the experiment： The integral optical density （IOD） was significantly increased,compared with those of normal tissues. The IOD level of the rectal cancer was associated with the Dukes stage, lymph node metastasis and distant metastasis （ P 〈0.05）. In Cox regression analysis, HIF-1α and VEGF were independent risk factors for prognosis. Conclusion Overexpression of HIF-1α is significantly associated with the angiogenesis in rectal cancer. The mechanism may be that the elevated level of HIF-1α induces the tumor angiogenesis by activating the transcription of VEGF gene. The study suggests that HIF-1α and VEGF may play important roles in rectal cancer progression.