Anti-Müllerian Hormone Signaling Regulates Epithelial Plasticity and Chemoresistance in Lung Cancer.
Anti-Müllerian Hormone Signaling Regulates Epithelial Plasticity and Chemoresistance in Lung Cancer.
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DOI：
10.1016/j.celrep.2016.06.043
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发表时间：
2016-07-19
期刊：
影响因子：
8.8
通讯作者：
Golemis EA
中科院分区：
文献类型：
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作者：
Beck TN;Korobeynikov VA;Kudinov AE;Georgopoulos R;Solanki NR;Andrews-Hoke M;Kistner TM;Pépin D;Donahoe PK;Nicolas E;Einarson MB;Zhou Y;Boumber Y;Proia DA;Serebriiskii IG;Golemis EA
抗苗勒管激素（AMH）及其II型受体AMHR 2，以前被认为主要在性腺组织中发挥作用，意外地被鉴定为肺癌中TGF-β/BMP信号传导和上皮-间质转化（EMT）的有效调节剂。AMH是TGF-β/BMP超家族成员，并且AMHR 2与I型受体（ALK 2、ALK 3）异二聚化，所述I型受体也被BMP的II型受体（BMPR 2）使用。AMH信号调节BMPR 2、ALK 2和ALK 3的表达，支持AKT-NFκB和SMAD存活信号，并影响NSCLC中BMP依赖性信号。AMH和AMHR 2选择性地在上皮细胞与间充质细胞中表达，AMH/AMHR 2的缺失诱导EMT。EMT的独立诱导减少了AMH和AMHR 2的表达。重要的是，与AMH或AMHR 2耗尽相关的EMT导致化学抗性，但使细胞对HSP 90抑制剂ganetespib敏感。AMH/AMHR 2轴的识别有助于进一步阐明TGF-β/BMP抗性相关信号传导，并为EMT的治疗靶向提供新的策略。Beck等人鉴定了非小细胞肺癌（NSCLC）中TGF-β/BMP超家族成员抗苗勒管激素（AMH）及其受体AMHR 2的活性信号传导，证明了AMH/AMHR 2在影响基础和BMP依赖性SMAD信号传导中的作用，该信号传导抑制上皮-间充质转化（EMT）并调节耐药性。
Anti-Müllerian hormone (AMH) and its type II receptor AMHR2, both previously thought to primarily function in gonadal tissue, were unexpectedly identified as potent regulators of TGF-β/BMP signaling and epithelial-mesenchymal transition (EMT) in lung cancer. AMH is a TGF-β/BMP superfamily member, and AMHR2 heterodimerizes with type I receptors (ALK2, ALK3) also used by the type II receptor for BMP (BMPR2). AMH signaling regulates expression of BMPR2, ALK2 and ALK3, supports AKT-NFκB and SMAD survival signaling, and influences BMP-dependent signaling in NSCLC. AMH and AMHR2 are selectively expressed in epithelial versus mesenchymal cells, and loss of AMH/AMHR2 induces EMT. Independent induction of EMT reduces expression of AMH and AMHR2. Importantly, EMT associated with depletion of AMH or AMHR2 results in chemoresistance, but sensitizes cells to the HSP90 inhibitor ganetespib. Recognition of this AMH/AMHR2 axis helps to further elucidate TGF-β/BMP resistance-associated signaling and suggests new strategies for therapeutic targeting of EMT. Beck et al. identify active signaling by the TGF-β/BMP superfamily member anti-Müllerian hormone (AMH) and its receptor AMHR2 in non-small cell lung cancer (NSCLC), demonstrating a role for AMH/AMHR2 in influencing the basal and BMP-dependent SMAD signaling that constrains epithelial-mesenchymal transition (EMT), and regulating drug resistance.