title: 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.
abstract: 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).
authors: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Institute for Medical Science, Chonbuk National University Medical School and Hospital, Jeonju, Jeonbuk, Republic of Korea.
authors: Xiang-Dan
authors: XD
authors: Cui
authors: Mi-Jin
authors: MJ
authors: Lee
authors: Jong-Hyun
authors: JH
authors: Kim
authors: Pei-Pei
authors: PP
authors: Hao
authors: Lan
authors: L
authors: Liu
authors: Goung-Ran
authors: GR
authors: Yu
authors: Dae-Ghon
authors: DG
authors: Kim
mesh_terms: D001650:Bile Duct Neoplasms / Q000378:metabolism*; D001653:Bile Ducts, Intrahepatic; D000081247:CSK Tyrosine-Protein Kinase; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D018281:Cholangiocarcinoma / Q000378:metabolism*; D004789:Enzyme Activation; D058750:Epithelial-Mesenchymal Transition; D051418:Focal Adhesion Kinase 2 / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D009362:Neoplasm Metastasis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D036104:Receptor, EphA2 / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D048490:raf Kinases / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D046912:Multiprotein Complexes; D036104:Receptor, EphA2; D000081247:CSK Tyrosine-Protein Kinase; D051418:Focal Adhesion Kinase 2; D019061:src-Family Kinases; C000631346:CSK protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D048490:raf Kinases