Hypoxia-inducible factor-1α promotes nonhypoxia-mediated proliferation in colon cancer cells and xenografts
Hypoxia-inducible factor-1α promotes nonhypoxia-mediated proliferation in colon cancer cells and xenografts
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DOI：
10.1158/0008-5472.can-05-2887
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发表时间：
2006-02-01
期刊：
影响因子：
11.2
通讯作者：
Dang, LH
中科院分区：
文献类型：
--
作者：
Dang, DT;Chen, F;Dang, LH
缺氧诱导因子-1 α。HIF-1 α是一种转录因子，可直接反式激活对实体瘤生长和代谢重要的基因。HIF-1 α在癌症中过表达，其表达水平与患者死亡率相关。HIT-let的合成或稳定性增加可由缺氧依赖性或缺氧非依赖性因素诱导。因此，HIF-1 α在非缺氧和缺氧癌细胞中都有表达。HIF-1 α在非低氧介导的癌细胞增殖中的作用仍然是推测性的。我们已经通过在HCT 116和RKO人结肠癌细胞中的靶向同源重组破坏了HLF-1 α。在体外和体内，HIF-1 α的缺失显著降低了非缺氧介导的细胞增殖。有趣的是，尽管HIF-1 α在体外促进细胞增殖和缺氧条件下的存活，但HIF-1 α表达的丧失并没有严重影响体内肿瘤异种移植物内的缺氧区室。为了进一步测试HIF-1 α在肿瘤区室中的作用，我们产生了HLF-1 α和血管内皮生长因子（VEGF）联合破坏的细胞。在所有异种移植物中，VEGF的破坏导致缺氧区室的显著扩张和生长延迟。尽管如此，HIF-1 α的存在或不存在并没有严重影响这些扩大的缺氧区室。这些数据提供了令人信服的证据，在结肠癌的一个子集中，（a）HIF-1 α。是体外和体内非低氧介导的细胞增殖的阳性因子，和（B）HIF-1 α是体外低氧条件下细胞增殖和存活的阳性因子，但在体内对肿瘤低氧区室没有显著贡献。
Hypoxia-inducible factor-1 alpha. (HIF-1 alpha) is a transcription factor that directly transactivates genes important for the growth and metabolism of solid tumors. HIF-1 alpha is overexpressed in cancer, and its level of expression is correlated with patient mortality. Increased synthesis or stability of HIT-let can be induced by hypoxia-dependent or hypoxia-independent factors. Thus, HIF-1 alpha is expressed in both nonhypoxic and hypoxic cancer cells. The role of HIF-1 alpha in nonhypoxia-mediated cancer cell proliferation remains speculative. We have disrupted HLF-1 alpha by targeted homologous recombination in HCT116 and RKO human colon cancer cells. Loss of HIF-1 alpha significantly reduced nonhypoxia-mediated cell proliferation in vitro and in vivo. Paradoxically, loss of HIF-1 alpha expression did not grossly affect the hypoxic compartments within tumor xenografts in vivo, although HIF-1 alpha promoted cell proliferation and survival under hypoxia in vitro. To further test the role of HIF-1 alpha within tumor compartments, we generated cells with combined disruptions of both HLF-1 alpha 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-1 alpha did not grossly affect these expanded hypoxic compartments. These data provide compelling evidence that, in a subset of colon cancers, (a) HIF-1 alpha. is a positive factor for nonhypoxia-mediated cell proliferation in vitro and in vivo and (b) HIF-1 alpha 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.