Feedback regulators of hypoxia-inducible factors and their role in cancer biology
Feedback regulators of hypoxia-inducible factors and their role in cancer biology
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DOI：
10.4161/cc.9.14.12249
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发表时间：
2010-07-15
期刊：
影响因子：
4.3
通讯作者：
Acker, Till
中科院分区：
文献类型：
--
作者：
Henze, Anne-Theres;Acker, Till
恶性肿瘤的特点是低氧区域(缺氧)。缺氧的肿瘤微环境通过关键的转录调节因子HIF-1α和HIF-2α激活一系列适应性反应，从而促进肿瘤的进展。传统上，这些因子通过促进肿瘤生长所必需的过程，如血管生成、糖酵解、转移和侵袭，以及分化和自我更新，与侵袭性肿瘤表型有关。值得注意的是，复杂的HIF途径还启动了导致细胞周期停滞或细胞死亡的抗肿瘤机制，这表明需要严格控制缺氧反应的程度和方向。这种控制对于肿瘤细胞存活的重要性通过一个复杂的正负反馈调节网络在mRNA、蛋白质和表观遗传水平上对HIF活性的复杂调节来说明。我们认为，这些反馈调节因子有助于灵活地调整和适应HIF激活的反应，以适应急性和慢性缺氧期间肿瘤内氧浓度的波动，并减少HIF途径中的肿瘤抑制成分。此外，HIF的反馈调节可在慢性缺氧条件下诱导从HIF-1α向HIF-2α的转换，这可能在调节肿瘤细胞分化和维持肿瘤干细胞方面具有重要作用。鉴于其在癌症生物学中的核心作用，HIF反馈调节因子可能代表着一个有吸引力的新的抗肿瘤治疗靶点，以克服肿瘤细胞死亡抵抗。
Malignant tumors are characterized by regions of low oxygen concentration (hypoxia). The hypoxic tumor microenvironment contributes to tumor progression by activating a set of adaptive responses via the key transcriptional regulators HIF-1 alpha and HIF-2 alpha. These factors have been traditionally linked to an aggressive tumor phenotype by promoting processes essential for tumor growth, such as angiogenesis, glycolysis, metastasis and invasion, as well as differentiation and self renewal. Notably, the complex HIF pathway also initiates anti-tumorigenic mechanisms that lead to cell cycle arrest or cell death, indicating the need for a stringent control of the extent and the direction of the hypoxia response. The importance of this control for tumor cell survival is illustrated by the intricate regulation of HIF activity at the mRNA, protein and epigenetic level by a complex network of positive and negative feedback regulators. We propose that these feedback regulators help to flexibly adjust and adapt HIF activated responses to the fluctuating oxygen concentrations within tumors during acute and chronic hypoxia and to curtail the tumor-suppressing components of the HIF pathway. Moreover, feedback regulation of HIF induces a switch from HIF-1 alpha to HIF-2 alpha driven responses under chronic hypoxia which may have essential functions in the regulation of tumor cell differentiation and tumor stem cell maintenance. Given their central role in cancer biology, HIF feedback regulators may represent an attractive and novel anti-tumor therapy target to overcome cell death resistance in tumors.