Institute of Neuropathology, University of Giessen, Giessen, Germany.
Institute of Cell Biology and Neuroscience and Buchmann Institute for Molecular Life Sciences (BMLS), University of Frankfurt, Frankfurt am Main, Germany.
Cancer Res. 2018 Apr 1;78(7):1805-1819. doi: 10.1158/0008-5472.CAN-17-1346. Epub 2018 Jan 16.
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 TGFβ or by promoter methylation, enhanced EMT and spontaneous metastasis via HIF-dependent upregulation of the EGFR ligand TGFα. In turn, TGFα 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. This study links the oxygen sensor PHD3 to metastasis and drug resistance in cancer, with implications for therapeutic improvement by targeting this system. .
肺癌是全球癌症相关死亡的主要原因，很大程度上是由于其高转移倾向和产生治疗耐药性。对缺氧和上皮-间充质转化（EMT）的适应性反应与肿瘤转移和耐药性有关，但人们对氧感应和 EMT 如何相互作用以控制这些癌症特征知之甚少。在这里，我们表明，氧传感器 PHD3 将低氧信号与肺部肿瘤微环境中的 EMT 调节联系起来。PHD3 受到诱导 EMT 的信号抑制，并且作为 EMT、转移和治疗耐药性的负调节剂。肿瘤中 PHD3 的耗竭可能由 EMT 诱导剂 TGFβ或启动子甲基化引起，通过 HIF 依赖性上调 EGFR 配体 TGFα，增强 EMT 和自发转移。反过来，TGFα 刺激 EGFR，增强 SMAD 信号，从而加强 EMT 和转移。在肺癌的临床标本中，PHD3 表达降低与预后不良以及对 EGFR 抑制剂（如厄洛替尼）的治疗耐药性有关。在肺癌细胞中重新表达 PHD3 可抑制 EMT 和转移，并恢复对厄洛替尼的敏感性。总之，我们的研究结果确立了 PHD3 在转移和耐药性中的关键作用，并表明通过干扰 PHD3 沉默激活的正反馈信号机制来改善患者治疗的机会。这项研究将氧传感器 PHD3 与癌症的转移和耐药性联系起来，为靶向该系统改善治疗提供了依据。
