Loss of PHD3 allows tumours to overcome hypoxic growth inhibition and sustain proliferation through EGFR.
Loss of PHD3 allows tumours to overcome hypoxic growth inhibition and sustain proliferation through EGFR.
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PHD3的损失使肿瘤可以克服低氧生长抑制并通过EGFR维持增殖。
DOI：
10.1038/ncomms6582
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发表时间：
2014-11-25
影响因子：
16.6
通讯作者：
Acker T
中科院分区：
文献类型：
--
作者：
Henze AT;Garvalov BK;Seidel S;Cuesta AM;Ritter M;Filatova A;Foss F;Dopeso H;Essmann CL;Maxwell PH;Reifenberger G;Carmeliet P;Acker-Palmer A;Acker T
实体瘤暴露于微环境因素，如通常抑制细胞生长的缺氧。然而，肿瘤细胞能够通过在很大程度上未知的机制抵消这些信号。在这里，我们表明，脯氨酰羟化酶PHD3抑制肿瘤生长的微环境线索，通过控制EGFR。人类神经胶质瘤中的PHD3沉默或小鼠高级星形细胞瘤模型中的基因缺失显著促进肿瘤生长和肿瘤在不利条件下继续生长的能力。PHD 3的生长抑制功能不依赖于已建立的PHD 3靶点HIF和NF-κ B及其羟化酶活性。相反，PHD3的缺失导致表皮生长因子受体（EGFR）的过度磷酸化。重要的是，PHD3的表观遗传/遗传沉默优先发生在没有EGFR扩增的胶质瘤中。我们的研究结果表明，PHD3失活提供了EGFR激活的替代途径，通过该途径，肿瘤细胞即使在有限的氧可用性条件下也能维持增殖信号。 关于实体瘤如何克服其缺氧微环境中的生长抑制信号知之甚少。Henze等人在这里表明，氧传感器PHD3在神经胶质瘤中经常丢失，并且这种丢失过度激活EGFR信号传导以维持肿瘤细胞增殖和在缺氧中存活。
Solid tumours are exposed to microenvironmental factors such as hypoxia that normally inhibit cell growth. However, tumour cells are capable of counteracting these signals through mechanisms that are largely unknown. Here we show that the prolyl hydroxylase PHD3 restrains tumour growth in response to microenvironmental cues through the control of EGFR. PHD3 silencing in human gliomas or genetic deletion in a murine high-grade astrocytoma model markedly promotes tumour growth and the ability of tumours to continue growing under unfavourable conditions. The growth-suppressive function of PHD3 is independent of the established PHD3 targets HIF and NF-κB and its hydroxylase activity. Instead, loss of PHD3 results in hyperphosphorylation of epidermal growth factor receptor (EGFR). Importantly, epigenetic/genetic silencing of PHD3 preferentially occurs in gliomas without EGFR amplification. Our findings reveal that PHD3 inactivation provides an alternative route of EGFR activation through which tumour cells sustain proliferative signalling even under conditions of limited oxygen availability. Little is known on how solid tumours overcome growth inhibitory signals within its hypoxic microenvironment. Here Henze et al. show that oxygen sensor PHD3 is frequently lost in gliomas, and that this loss hyperactivates EGFR signaling to sustain tumour cell proliferation and survival in hypoxia.
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影响因子：
16.6
作者：
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