Activation of mammalian target of rapamycin complex 1 (mTORC1) and Raf/Pyk2 by growth factor-mediated Eph receptor 2 (EphA2) is required for cholangiocarcinoma growth and metastasis
Activation of mammalian target of rapamycin complex 1 (mTORC1) and Raf/Pyk2 by growth factor-mediated Eph receptor 2 (EphA2) is required for cholangiocarcinoma growth and metastasis
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生长因子介导的 Eph 受体 2 (EphA2) 激活哺乳动物雷帕霉素复合物靶标 1 (mTORC1) 和 Raf/Pyk2，是胆管癌生长和转移所必需的
DOI：
10.1002/hep.26253
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发表时间：
2013-06-01
期刊：
影响因子：
13.5
通讯作者：
Kim, Dae-Ghon
中科院分区：
文献类型：
--
作者：
Cui, Xiang-Dan;Lee, Mi-Jin;Kim, Dae-Ghon
在肿瘤进展过程中，Eph受体2(EphA2)的过度表达常常伴随着其同源配体的丢失。然而，在高度恶性和致命性胆管细胞癌(CC)中，EphA2这种非配体依赖性促肿瘤的分子机制尚不清楚。我们根据肿瘤分化程度检测了EphA2在肿瘤生长和转移中的生物学作用，并探索了EphA2的下游信号通路。生长因子介导的EphA2过表达本身导致哺乳动物靶标雷帕霉素复合体1(MTORC1)和细胞外信号调节激酶(ERK)途径的激活，这是通过EphA2的配体非依赖性激活(S897的磷酸化)实现的。体外软琼脂实验和体内原位或皮下肿瘤模型显示，EphA2促进集落形成和促进肿瘤生长，并可能主要与Akt(T308)/mTORC1激活有关。EphA2的异常表达和激活也与分化较差和转移能力高有关。在原位肿瘤模型或肺转移模型中也观察到转移能力增强，除了激活典型的Raf/MEK/ERK通路外，还与Pyk2(Y402)/c-Src/ERK激活有关。MTORC1和Raf/Pyk2通路似乎也相互影响。这些结果提示，生长因子介导的EphA2可能通过激活mTORC1和Raf/Pyk2通路参与肿瘤的生长和转移。针对EphA2及其下游效应分子的治疗策略可能对控制CC有用。(《肝病》2013；57：2248-2260)
Eph receptor 2 (EphA2) overexpression is frequently accompanied by the loss of its cognate ligand during tumor progression. However, the molecular mechanism of this ligand-independent promotion of tumor by EphA2 remains unclear in highly malignant and fatal cholangiocarcinoma (CC). We examined the biological role of EphA2 in tumor growth and metastasis in CC tissues and cells according to the degree of differentiation and we explored the downstream signaling pathways of EphA2. Growth factor-mediated EphA2 overexpression itself leads to the activation of the mammalian target of rapamycin complex 1 (mTORC1) and extracellular signal-regulated kinase (ERK) pathways through ligand-independent activation of EphA2 (phosphorylation of S897). An in vitro soft agar assay and in vivo orthotopic or subcutaneous tumor model showed that EphA2 enhanced colony formation and accelerated tumor growth, and which seemed to be mainly associated with Akt (T308)/mTORC1 activation. Aberrant expression and activation of EphA2 was also associated with poorer differentiation and higher metastatic ability. Enhanced metastatic ability was also observed in an orthotopic tumor model or lung metastasis model, correlating with Pyk2(Y402)/c-Src/ERK activation in addition to activation of the canonical Raf/MEK/ERK pathway. The mTORC1 and Raf/Pyk2 pathways also appeared to affect each other. These results suggest that growth factor-mediated EphA2 might be involved in tumor growth and metastasis through activation of the mTORC1 and Raf/Pyk2 pathways. Therapeutic strategies that target EphA2 and its downstream effectors may be useful to control CC. (HEPATOLOGY 2013;57:2248-2260)