Ciliary Neurotrophic Factor Receptor a Subunit–Modulated Multiple Downstream Signaling Pathways in Hepatic Cancer Cell Lines and Their Biological Implications
Xin Hu,1,2* Yingjun Zhao,1,2* Xianghuo He,2 Jinjun Li,2 Tao Wang,1,2 Weiping Zhou,3 Dafang Wan,2 Hongyang Wang,2 and Jianren Gu2
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 CNTFRa is expressed heterogeneously in normal human liver and hepatocellular carcinoma (HCC) specimens but not in hepatoblastoma specimens. We choose the CNTFRa+/CNTFRa- (CNTFRa positive/ CNTFRa negative) cell models of hepatic origin to study multiple downstream pathways of CNTFRa. We show that the presence of CNTFRa 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 underCNTFstimulation, 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 CNTFRa and is modulated by the glucose concentration of the culture medium.
Conclusion: Our results demonstrate the importance of CNTFRa-mediated downstream signaling pathways and their functional implications in hepatic cancer cells, thus highlighting a better understanding of the biological roles of CNTFRa in human liver abnormalities, including metabolic diseases and hepatocarcinogenesis. (HEPATOLOGY 2008;47:1298-1308.)