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Ciliary neurotrophic factor receptor α subunit–modulated multiple downstream signaling pathways in hepatic cancer cell lines and their biological implications
Author(s) -
Hu Xin,
Zhao Yingjun,
He Xianghuo,
Li Jinjun,
Wang Tao,
Zhou Weiping,
Wan Dafang,
Wang Hongyang,
Gu Jianren
Publication year - 2008
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.22163
Subject(s) - ciliary neurotrophic factor , microbiology and biotechnology , ampk , biology , signal transduction , protein kinase a , neurotrophic factors , cancer research , receptor , kinase , biochemistry
Abstract Ciliary neurotrophic factor (CNTF) plays important roles in a variety of tissues including neural and non‐neural systems, but the function of CNTF and its receptor (CNTFR) in liver remains unclear. In this study, we demonstrate that CNTFRα is expressed heterogeneously in normal human liver and hepatocellular carcinoma (HCC) specimens but not in hepatoblastoma specimens. We choose the CNTFRα + /CNTFRα − (CNTFRα positive/ CNTFRα negative) cell models of hepatic origin to study multiple downstream pathways of CNTFRα. We show that the presence of CNTFRα determines the temporal activation patterns of downstream signaling molecules and serves as a key modulator in regulating PI3K and AMP–activated protein kinase (AMPK) dynamically under CNTF stimulation, thus resulting in the increase of glucose uptake and translocation of glucose transporter 4 (GLUT4). Furthermore, CNTF‐induced mitogen‐activated protein kinase (MAPK) activation suppresses AMPK activity in the early phase of CNTF stimulation. Moreover, the protective role of CNTF against cell‐cycle arrest is dependent on the presence of CNTFRα and is modulated by the glucose concentration of the culture medium. Conclusion: Our results demonstrate the importance of CNTFRα‐mediated downstream signaling pathways and their functional implications in hepatic cancer cells, thus highlighting a better understanding of the biological roles of CNTFRα in human liver abnormalities, including metabolic diseases and hepatocarcinogenesis. (H EPATOLOGY 2008.)