Lian Zhaorui, Liu Jie, Wu Mengchao, Wang Hong-Yang, Arbuthnot Patrick, Kew Michael, Feitelson Mark A
Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, 1020 Locust Street, Philadelphia, PA 19107, USA.
Hepatology. 2007 Jun;45(6):1390-9. doi: 10.1002/hep.21610.
Hepatitis B x antigen (HBxAg) is a trans-activating protein that contributes to liver cancer, in part, by altering the expression of cellular genes. However, few natural effectors of HBxAg have been identified. Hence, HBxAg positive and negative HepG2 cells were prepared and analyzed by PCR select cDNA subtraction. The results identified elevated vascular endothelial growth factor receptor-3 short form splice variant (VEGFR-3(S)) expression in HBxAg positive compared to negative cells. Normally, VEGFR-3 activates Akt signaling in lymphatic endothelial cells, resulting in lymphangiogenesis. In contrast, the results here show that the expression of VEGFR-3(S) is up-regulated in >75% of HBxAg positive hepatocellular carcinoma (HCC) nodules. VEGFR-3(S) up-regulation correlates with the expression of HBxAg, is associated with decreased survival in tumor bearing patients, and when over-expressed in HepG2 cells, strongly stimulated cell growth in culture, in soft agar, and accelerated tumor formation in a ligand independent manner. VEGFR-3(S) siRNA partially blocked the ability of HBxAg to promote hepatocellular growth. In conclusion, HBxAg may short circuit VEGFR-3(S) signaling in liver cancer. Blocking VEGFR-3(S) signaling may be effective in preventing tumor development and/or prolonging survival in tumor bearing patients.
乙型肝炎X抗原（HBxAg）是一种反式激活蛋白，部分通过改变细胞基因的表达促成肝癌。然而，已鉴定出的HBxAg天然效应分子很少。因此，制备了HBxAg阳性和阴性的HepG2细胞，并通过PCR选择cDNA消减技术进行分析。结果显示，与阴性细胞相比，HBxAg阳性细胞中血管内皮生长因子受体-3短型剪接变体（VEGFR-3(S)）的表达升高。正常情况下，VEGFR-3在淋巴管内皮细胞中激活Akt信号传导，导致淋巴管生成。相反，此处结果表明，在超过75%的HBxAg阳性肝细胞癌（HCC）结节中，VEGFR-3(S)的表达上调。VEGFR-3(S)的上调与HBxAg的表达相关，与荷瘤患者生存率降低有关，并且当在HepG2细胞中过表达时，能以不依赖配体的方式强烈刺激培养中的细胞生长、软琼脂中的细胞生长并加速肿瘤形成。VEGFR-3(S) siRNA部分阻断了HBxAg促进肝细胞生长的能力。总之，HBxAg可能在肝癌中使VEGFR-3(S)信号传导短路。阻断VEGFR-3(S)信号传导可能对预防肿瘤发展和/或延长荷瘤患者的生存期有效。
