Activation of HIF-1α does not increase intestinal tumorigenesis.
Activation of HIF-1α does not increase intestinal tumorigenesis.
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DOI：
10.1152/ajpgi.00112.2014
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发表时间：
2014-07
期刊：
影响因子：
--
通讯作者：
Xiang Xue;S. Ramakrishnan;Y. Shah
中科院分区：
文献类型：
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作者：
Xiang Xue;S. Ramakrishnan;Y. Shah
缺氧反应由两个转录因子--缺氧诱导因子（HIF）-1α和HIF-2α介导。这些高度同源的转录因子在缺氧灶中被诱导并调节细胞代谢、血管生成、细胞增殖和细胞存活。HIF-1α和HIF-2α在癌症进展的早期被激活，在肿瘤生物学的几个方面很重要。HIF-1α和HIF-2α具有相互重叠和不同的功能。在肠道中，HIF-2α的激活增加了小鼠模型中的炎症和结肠癌发生。有趣的是，在肠道缺血性和炎症性疾病中，HIF-1α的激活是有益的，可以减少肠道炎症。HIF-1α是炎症后调节上皮屏障功能的关键转录因子。由于HIF的致瘤潜力，长期激活HIF-1α的药理学药物的有益价值降低。本研究验证了HIF-1α的慢性激活可能促进结肠肿瘤发生的假设。评估了两种结肠癌模型，散发性和结肠炎相关结肠癌模型。肠上皮细胞中HIF-1α的激活不会增加结肠癌的发生或进展。总之，这些数据提供了原则证据，即HIF-1α的药理学激活可能是炎症性肠病的安全治疗策略。
The hypoxic response is mediated by two transcription factors, hypoxia-inducible factor (HIF)-1α and HIF-2α. These highly homologous transcription factors are induced in hypoxic foci and regulate cell metabolism, angiogenesis, cell proliferation, and cell survival. HIF-1α and HIF-2α are activated early in cancer progression and are important in several aspects of tumor biology. HIF-1α and HIF-2α have overlapping and distinct functions. In the intestine, activation of HIF-2α increases inflammation and colon carcinogenesis in mouse models. Interestingly, in ischemic and inflammatory diseases of the intestine, activation of HIF-1α is beneficial and can reduce intestinal inflammation. HIF-1α is a critical transcription factor regulating epithelial barrier function following inflammation. The beneficial value of pharmacological agents that chronically activate HIF-1α is decreased due to the tumorigenic potential of HIFs. The present study tested the hypothesis that chronic activation of HIF-1α may enhance colon tumorigenesis. Two models of colon cancer were assessed, a sporadic and a colitis-associated colon cancer model. Activation of HIF-1α in intestinal epithelial cells does not increase carcinogenesis or progression of colon cancer. Together, the data provide proof of principle that pharmacological activation of HIF-1α could be a safe therapeutic strategy for inflammatory bowel disease.