Dang Duyen T, Chen Fang, Gardner Lawrence B, Cummins Jordan M, Rago Carlo, Bunz Fred, Kantsevoy Sergey V, Dang Long H
Division of Gastroenterology, Department of Internal Medicine, University of Michigan Medical Center, 1150 West Medical Center Drive, Ann Arbor, MI 48109, USA.
Cancer Res. 2006 Feb 1;66(3):1684-936. doi: 10.1158/0008-5472.CAN-05-2887.
Hypoxia-inducible factor-1alpha (HIF-1alpha) is a transcription factor that directly transactivates genes important for the growth and metabolism of solid tumors. HIF-1alpha is overexpressed in cancer, and its level of expression is correlated with patient mortality. Increased synthesis or stability of HIF-1alpha can be induced by hypoxia-dependent or hypoxia-independent factors. Thus, HIF-1alpha is expressed in both nonhypoxic and hypoxic cancer cells. The role of HIF-1alpha in nonhypoxia-mediated cancer cell proliferation remains speculative. We have disrupted HIF-1alpha by targeted homologous recombination in HCT116 and RKO human colon cancer cells. Loss of HIF-1alpha significantly reduced nonhypoxia-mediated cell proliferation in vitro and in vivo. Paradoxically, loss of HIF-1alpha expression did not grossly affect the hypoxic compartments within tumor xenografts in vivo, although HIF-1alpha promoted cell proliferation and survival under hypoxia in vitro. To further test the role of HIF-1alpha within tumor compartments, we generated cells with combined disruptions of both HIF-1alpha and vascular endothelial growth factor (VEGF). In all xenografts, disruption of VEGF led to marked expansion of the hypoxic compartments and growth delay. Nonetheless, the presence or absence of HIF-1alpha did not grossly affect these expanded hypoxic compartments. These data provide compelling evidence that, in a subset of colon cancers, (a) HIF-1alpha is a positive factor for nonhypoxia-mediated cell proliferation in vitro and in vivo and (b) HIF-1alpha is a positive factor for cell proliferation and survival under hypoxic conditions in vitro, but does not grossly contribute to the tumor hypoxic compartments in vivo.
缺氧诱导因子-1α（HIF-1α）是一种转录因子，可直接反式激活对实体瘤生长和代谢至关重要的基因。HIF-1α在癌症中过度表达，其表达水平与患者死亡率相关。HIF-1α合成或稳定性的增加可由缺氧依赖性或缺氧非依赖性因素诱导。因此，HIF-1α在非缺氧和缺氧癌细胞中均有表达。HIF-1α在非缺氧介导的癌细胞增殖中的作用仍具有推测性。我们通过在HCT116和RKO人结肠癌细胞中进行靶向同源重组来破坏HIF-1α。HIF-1α的缺失显著降低了体外和体内非缺氧介导的细胞增殖。矛盾的是，尽管HIF-1α在体外缺氧条件下促进细胞增殖和存活，但HIF-1α表达的缺失并未对体内肿瘤异种移植物中的缺氧区域产生明显影响。为了进一步测试HIF-1α在肿瘤区域中的作用，我们生成了同时破坏HIF-1α和血管内皮生长因子（VEGF）的细胞。在所有异种移植物中，VEGF的破坏导致缺氧区域明显扩大和生长延迟。尽管如此，HIF-1α的存在与否并未对这些扩大的缺氧区域产生明显影响。这些数据提供了令人信服的证据，即在一部分结肠癌中，（a）HIF-1α是体外和体内非缺氧介导的细胞增殖的正向因子，（b）HIF-1α是体外缺氧条件下细胞增殖和存活的正向因子，但对体内肿瘤缺氧区域的贡献不大。
