PHD3 Controls Lung Cancer Metastasis and Resistance to EGFR Inhibitors through TGFα
PHD3 Controls Lung Cancer Metastasis and Resistance to EGFR Inhibitors through TGFα
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DOI：
10.1158/0008-5472.can-17-1346
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发表时间：
2018-04-01
期刊：
影响因子：
11.2
通讯作者：
Acker, Till
中科院分区：
文献类型：
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作者：
Dopeso, Higinio;Jiao, Hui-Ke;Acker, Till
肺癌是世界范围内癌症相关死亡的主要原因，这在很大程度上是由于其高转移倾向和产生耐药性。对缺氧和上皮-间质转化（EMT）的适应性反应与肿瘤转移和耐药性有关，但对氧传感和EMT如何交叉控制这些癌症标志知之甚少。在这里，我们表明氧传感器PHD 3连接缺氧信号和EMT调节肺肿瘤微环境。PHD 3被诱导EMT的信号抑制，并充当EMT、转移和治疗抗性的负调节剂。肿瘤中的PHD 3耗竭，其可由EMT诱导剂TGF β或启动子甲基化引起，通过EGFR配体TGF α的HIF依赖性上调增强EMT和自发转移。反过来，TGF α刺激EGFR，其增强SMAD信号传导，加强EMT和转移。在肺癌的临床标本中，PHD 3表达减少与预后不良和对EGFR抑制剂如厄洛替尼的治疗耐药性有关。PHD 3在肺癌细胞中的重新表达抑制了EMT和转移，并恢复了对厄洛替尼的敏感性。两者合计，我们的研究结果建立了一个关键的功能，PHD 3在转移和耐药性，并提出机会，以改善患者的治疗，通过干扰前馈信号机制激活PHD 3 silencing.Significance：这项研究将氧传感器PHD 3转移和耐药性的癌症，通过靶向这个系统的治疗改善的影响。(C)2018年AACR。
Lung cancer is the leading cause of cancer-related death worldwide, in large part due to its high propensity to metastasize and to develop therapy resistance. Adaptive responses to hypoxia and epithelial-mesenchymal transition (EMT) are linked to tumor metastasis and drug resistance, but little is known about how oxygen sensing and EMT intersect to control these hallmarks of cancer. Here, we show that the oxygen sensor PHD3 links hypoxic signaling and EMT regulation in the lung tumor microenvironment. PHD3 was repressed by signals that induce EMT and acted as a negative regulator of EMT, metastasis, and therapeutic resistance. PHD3 depletion in tumors, which can be caused by the EMT inducer TGF beta or by promoter methylation, enhanced EMT and spontaneous metastasis via HIF-dependent upregulation of the EGFR ligand TGF alpha. In turn, TGF alpha stimulated EGFR, which potentiated SMAD signaling, reinforcing EMT and metastasis. In clinical specimens of lung cancer, reduced PHD3 expression was linked to poor prognosis and to therapeutic resistance against EGFR inhibitors such as erlotinib. Reexpression of PHD3 in lung cancer cells suppressed EMT and metastasis and restored sensitivity to erlotinib. Taken together, our results establish a key function for PHD3 in metastasis and drug resistance and suggest opportunities to improve patient treatment by interfering with the feedforward signaling mechanisms activated by PHD3 silencing.Significance: This study links the oxygen sensor PHD3 to metastasis and drug resistance in cancer, with implications for therapeutic improvement by targeting this system. (C) 2018 AACR.