Laboratory of Molecular Oncology, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Hepatology. 2010 Feb;51(2):535-44. doi: 10.1002/hep.23313.
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.
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.
Eph/Ephrin 家族是受体酪氨酸激酶家族中最大的家族之一，在形态发生和神经发育中得到了广泛的研究。最近，人们越来越关注它在各种癌症的发生和进展中的作用。然而，Eph/Ephrins 在肝细胞癌 (HCC) 中的作用很少被研究。在这项研究中，我们发现 EphrinA2 的表达在 HCC 的已建立细胞系和临床组织样本中均显著上调，在门静脉侵袭的肿瘤中观察到最显著的增加。EphrinA2 在 HCC 细胞中的强制表达显著促进体内肿瘤发生，而敲低该基因则抑制了这种致癌作用。我们进一步发现，抑制细胞凋亡而不是加速增殖是 EphrinA2 增强肿瘤发生的原因。此外，EphrinA2 赋予癌细胞对肿瘤坏死因子 alpha (TNF-alpha) 诱导的细胞凋亡的抗性，从而促进其存活。此外，我们揭示了一个新的 EphrinA2/ras 相关 C3 肉毒杆菌毒素底物 1 (Rac1)/V-akt 鼠胸腺病毒致癌基因同源物 (Akt)/核因子-kappa B (NF-kappaB) 通路，该通路有助于抑制 HCC 细胞中的细胞凋亡。
这项研究表明 EphrinA2 通过促进癌细胞的存活在 HCC 的发展和进展中起重要作用，表明其在 HCC 中作为潜在治疗靶点的作用。
