HIF1A Overexpression Is Associated with Poor Prognosis in a Cohort of 731 Colorectal Cancers
HIF1A Overexpression Is Associated with Poor Prognosis in a Cohort of 731 Colorectal Cancers
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DOI：
10.2353/ajpath.2010.090972
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发表时间：
2010-05-01
影响因子：
6
通讯作者：
Ogino, Shuji
中科院分区：
文献类型：
--
作者：
Baba, Yoshifumi;Nosho, Katsuhiko;Ogino, Shuji
组织缺氧通常发生在肿瘤中。缺氧诱导因子（HIF）-1和HIF-2是细胞对缺氧反应的重要介质，调节肿瘤血管生成、葡萄糖代谢和抗氧化应激的基因表达。它们的关键调节亚基HIF 1A（HIF-1 α）和内皮PAS结构域蛋白1（EPAS 1; HIF-2 α）过度表达，并与多种癌症的患者预后相关。然而，结肠癌与HIF表达的预后或分子特征仍然不确定。在两项前瞻性队列研究的731例结直肠癌中，142例（19%）肿瘤显示HIF 1A过表达，322例（46%）肿瘤显示EPAS 1过表达。在Kaplan-Meier分析中，HIF 1A过表达与较高的结直肠癌特异性死亡率显著相关（对数秩检验，P < 0.0001），单变量考克斯回归（风险比= 1.84; 95%置信区间，1.37至2.47; P < 0.0001）和多变量分析（调整后的风险比= 1.72; 95%置信区间，1.26至2.36; P = 0.0007），调整了临床和肿瘤特征，包括微卫星不稳定性，TP 53（p53），PTGS 2（环氧合酶-2）、CpG岛甲基化表型和KRAS、BRAF、PIK 3C 4和LINE-1甲基化。相比之下，EPAS 1表达与患者生存率无显著相关性。此外，HIF 1A表达与PTGS 2表达（P = 0.0035）、CpG岛甲基化表型高（P = 0.013）和LINE-1低甲基化（P = 0.017）独立相关。EPAS 1表达与高肿瘤分级（P = 0.0017）和肥胖（体重指数>= 30 kg/m2）（P = 0.039）呈负相关。总之，HIF 1A表达与结直肠癌预后不良独立相关，提示HIF 1A作为生物标志物具有潜在的重要治疗意义。(Am J Pathol 2010，176：2292-2301; DOI：10.2353/ajpath.2010.090972）
Tissue hypoxia commonly occurs in tumors. Hypoxia-inducible factor (HIF)-1 and HIF-2, which are essential mediators of cellular response to hypoxia, regulate gene expression for tumor angiogenesis, glucose metabolism, and resistance to oxidative stress. Their key regulatory subunits, HIF1A (HIF-1 alpha) and endothelial PAS domain protein 1 (EPAS1; HIF-2 alpha), are over-expressed and associated with patient prognosis in a variety of cancers. However, prognostic or molecular features of colon cancer with HIF expression remain uncertain. Among 731 colorectal cancers in two prospective cohort studies, 142 (19%) tumors showed HIF1A overexpression, and 322 (46%) showed EPAS1 overexpression by immunohistochemistry. HIF1A overexpression was significantly associated with higher colorectal cancer-specific mortality in Kaplan-Meier analysis (log-rank test, P < 0.0001), univariate Cox regression (hazard ratio = 1.84; 95% confidence interval, 1.37 to 2.47; P < 0.0001) and multivariate analysis (adjusted hazard ratio = 1.72; 95% confidence interval, 1.26 to 2.36; P = 0.0007) that adjusted for clinical and tumoral features, including microsatellite instability, TP53 (p53), PTGS2 (cyclooxygenase-2), CpG island methylator phenotype, and KRAS, BRAF, PIK3C4, and LINE-1 methylation. In contrast, EPAS1 expression was not significantly associated with patient survival. In addition, HIF1A expression was independently associated with PTGS2 expression (P = 0.0035), CpG island methylator phenotype-high (P = 0.013), and LINE-1 hypomethylation (P = 0.017). EPAS1 expression was inversely associated with high tumor grade (P = 0.0017) and obesity (body mass index >= 30 kg/m(2))(P = 0.039). In conclusion, HIF1A expression is independently associated with poor prognosis in colorectal cancer, suggesting HIF1A as a biomarker with potentially important therapeutic implications. (Am J Pathol 2010, 176:2292-2301; DOI: 10.2353/ajpath.2010.090972)