Liver cancer: EphrinA2 promotes tumorigenicity through Rac1/Akt/NF-kappaB signaling pathway.
Eph/Ephrin family, one of the largest receptor tyrosine kinase families, has been extensively studied in morphogenesis and neural development. Recently, growing attention has been paid to its role in the initiation and progression of various cancers. However, the role of Eph/Ephrins in hepatocellular carcinoma (HCC) has been rarely investigated. In this study, we found that the expression of EphrinA2 was significantly up-regulated in both established cell lines and clinical tissue samples of HCC, and the most significant increase was observed in the tumors invading the portal veins. Forced expression of EphrinA2 in HCC cells significantly promoted in vivo tumorigenicity, whereas knockdown of this gene inhibited this oncogenic effect. We further found that suppression of apoptosis, rather than accelerating proliferation, was responsible for EphrinA2-enhanced tumorigenicity. In addition, EphrinA2 endowed cancer cells with resistance to tumor necrosis factor alpha (TNF-alpha)-induced apoptosis, thus facilitating their survival. Furthermore, we disclosed a novel EphrinA2/ras-related c3 botulinum toxin substrate 1 (Rac1)/V-akt murine thymoma viral oncogene homolog (Akt)/nuclear factor-kappa B (NF-kappaB) pathway contributing to the inhibitory effect on apoptosis in HCC cells.


CONCLUSIONS
This study revealed that EphrinA2 played an important role in the development and progression of HCC by promoting the survival of cancer cells, indicating its role as a potential therapeutic target in HCC.
Feng
Yu-Xiong
YX
Laboratory of Molecular Oncology, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Zhao
Jiang-Sha
JS
Li
Jing-Jing
JJ
Wang
Tao
T
Cheng
Shu-Qun
SQ
Yuan
Yunfei
Y
Wang
Fudi
F
Wang
Xiao-Fan
XF
Xie
Dong
D
D006528:Carcinoma, Hepatocellular / Q000209:etiology*; D045744:Cell Line, Tumor; D036383:Ephrin-A2 / Q000502:physiology*; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000209:etiology*; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D015398:Signal Transduction; D020830:rac1 GTP-Binding Protein / Q000502:physiology*
D036383:Ephrin-A2; D016328:NF-kappa B; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D020830:rac1 GTP-Binding Protein