Document Detail

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.
MedLine Citation:
PMID:  23315987     Owner:  NLM     Status:  MEDLINE    
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).
Xiang-Dan Cui; Mi-Jin Lee; Jong-Hyun Kim; Pei-Pei Hao; Lan Liu; Goung-Ran Yu; Dae-Ghon Kim
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Hepatology (Baltimore, Md.)     Volume:  57     ISSN:  1527-3350     ISO Abbreviation:  Hepatology     Publication Date:  2013 Jun 
Date Detail:
Created Date:  2013-06-13     Completed Date:  2013-08-16     Revised Date:  2013-09-30    
Medline Journal Info:
Nlm Unique ID:  8302946     Medline TA:  Hepatology     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2248-60     Citation Subset:  IM    
Copyright Information:
Copyright © 2013 American Association for the Study of Liver Diseases.
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.
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MeSH Terms
Bile Duct Neoplasms / metabolism*
Bile Ducts, Intrahepatic*
Cell Line, Tumor
Cell Transformation, Neoplastic
Cholangiocarcinoma / metabolism*
Enzyme Activation
Epithelial-Mesenchymal Transition
Focal Adhesion Kinase 2 / metabolism
Gene Knockdown Techniques
Neoplasm Metastasis
Proto-Oncogene Proteins c-akt / metabolism
Receptor, EphA2 / metabolism*
TOR Serine-Threonine Kinases / metabolism*
raf Kinases / metabolism
src-Family Kinases / metabolism
Reg. No./Substance:
0/mechanistic target of rapamycin complex 1; EC Serine-Threonine Kinases; EC, EphA2; EC tyrosine-protein kinase; EC Adhesion Kinase 2; EC Kinases; EC Proteins c-akt; EC Kinases

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