Department of Cancer Research, Key Laboratory of Molecular Microbiology and Technology of Ministry of Education, Institute for Molecular Biology, College of Life Sciences, Nankai University, Tianjin, People's Republic of China.
PLoS One. 2012;7(2):e31458. doi: 10.1371/journal.pone.0031458. Epub 2012 Feb 15.
Hepatitis B virus X protein (HBx) plays an important role in the development of hepatocellular carcinoma (HCC). However, the mechanism remains unclear. Recently, we have reported that HBx promotes hepatoma cell migration through the upregulation of calpain small subunit 1 (Capn4). In addition, several reports have revealed that osteopontin (OPN) plays important roles in tumor cell migration. In this study, we investigated the signaling pathways involving the promotion of cell migration mediated by HBx. We report that HBx stimulates several factors in a network manner to promote hepatoma cell migration. We showed that HBx was able to upregulate the expression of osteopontin (OPN) through 5-lipoxygenase (5-LOX) in HepG2-X/H7402-X (stable HBx-transfected cells) cells. Furthermore, we identified that HBx could increase the expression of 5-LOX through nuclear factor-κB (NF-κB). We also found that OPN could upregulate Capn4 through NF-κB. Interestingly, we showed that Capn4 was able to upregulate OPN through NF-κB in a positive feedback manner, suggesting that the OPN and Capn4 proteins involving cell migration affect each other in a network through NF-κB. Importantly, NF-κB plays a crucial role in the regulation of 5-LOX, OPN and Capn4. Thus, we conclude that HBx drives multiple cross-talk cascade loops involving NF-κB, 5-LOX, OPN and Capn4 to promote cell migration. This finding provides new insight into the mechanism involving the promotion of cell migration by HBx.
乙型肝炎病毒 X 蛋白 (HBx) 在肝细胞癌 (HCC) 的发展中起着重要作用。然而，其机制尚不清楚。最近，我们报道 HBx 通过上调钙蛋白酶小亚基 1 (Capn4) 促进肝癌细胞迁移。此外，有几项报道揭示了骨桥蛋白 (OPN) 在肿瘤细胞迁移中发挥重要作用。在这项研究中，我们研究了涉及 HBx 介导的细胞迁移促进的信号通路。我们报告 HBx 以网络方式刺激几种因子促进肝癌细胞迁移。我们表明 HBx 能够通过 5-脂氧合酶 (5-LOX) 在 HepG2-X/H7402-X(稳定转染 HBx 的细胞)中上调骨桥蛋白 (OPN) 的表达。此外，我们确定 HBx 可以通过核因子-κB (NF-κB) 增加 5-LOX 的表达。我们还发现 OPN 可以通过 NF-κB 上调 Capn4。有趣的是，我们表明 Capn4 能够通过 NF-κB 以正反馈方式上调 OPN，表明参与细胞迁移的 OPN 和 Capn4 蛋白通过 NF-κB 在网络中相互影响。重要的是，NF-κB 在调节 5-LOX、OPN 和 Capn4 中起着关键作用。因此，我们得出结论，HBx 驱动涉及 NF-κB、5-LOX、OPN 和 Capn4 的多个交叉对话级联环以促进细胞迁移。这一发现为 HBx 促进细胞迁移的机制提供了新的见解。
