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, PR China.
Neoplasia. 2010 Feb;12(2):103-15. doi: 10.1593/neo.91298.
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. Hepatitis B virus X protein (HBx) contributes to the development of HCC, whereas HBx with COOH-terminal deletion is a frequent event in the HCC tissues. Previously, we identified a natural mutant of HBx-truncated 27 amino acids at the COOH-terminal (termed HBxDelta127), which strongly enhanced cell growth. In the present study, we focused on investigating the mechanism. Accordingly, fatty acid synthase (FAS) plays a crucial role in cancer cell survival and proliferation; thus, we examined the signaling pathways involving FAS. Our data showed that HBxDelta127 strongly increased the transcriptional activities of FAS in human hepatoma HepG2 and H7402 cells. Moreover, we found that 5-lipoxygenase (5-LOX) was responsible for the up-regulation of FAS by using MK886 (an inhibitor of 5-LOX) and 5-LOX small interfering RNA. We observed that HBxDelta127 could upregulate 5-LOX through phosphorylated extracellular signal-regulated protein kinases 1/2 and thus resulted in the increase of released leukotriene B4 (LTB4, a metabolite of 5-LOX) by ELISA. The additional LTB4 could upregulate the expression of FAS in the cells as well. Interestingly, we found that FAS was able to upregulate the expression of 5-LOX in a feedback manner by using cerulenin (an inhibitor of FAS). Collectively, HBxDelta127 promotes cell growth through a positive feedback loop involving 5-LOX and FAS, in which released LTB4 is involved in the up-regulation of FAS. Thus, our finding provides a new insight into the mechanism involving the promotion of cell growth mediated by HBxDelta127.
肝细胞癌 (HCC) 是全球最常见的恶性肿瘤之一。乙型肝炎病毒 X 蛋白 (HBx) 促进 HCC 的发展，而 HBx 羧基末端缺失是 HCC 组织中的常见事件。先前，我们鉴定出 HBx 羧基末端截断 27 个氨基酸的天然突变体 (称为 HBxDelta127)，其强烈促进细胞生长。在本研究中，我们专注于研究其机制。脂肪酸合酶 (FAS) 在癌细胞的存活和增殖中起着至关重要的作用；因此，我们检查了涉及 FAS 的信号通路。我们的数据表明，HBxDelta127 强烈增加了人肝癌 HepG2 和 H7402 细胞中 FAS 的转录活性。此外，我们发现使用 MK886（5-LOX 的抑制剂）和 5-LOX 小干扰 RNA，5-脂氧合酶 (5-LOX) 负责 FAS 的上调。我们观察到 HBxDelta127 可以通过磷酸化细胞外信号调节蛋白激酶 1/2 来上调 5-LOX，从而导致 ELISA 检测到释放的白三烯 B4 (LTB4，5-LOX 的代谢物) 增加。额外的 LTB4 也可以上调细胞中 FAS 的表达。有趣的是，我们发现 FAS 可以通过 cerulenin（FAS 的抑制剂）以反馈方式上调 5-LOX 的表达。总之，HBxDelta127 通过涉及 5-LOX 和 FAS 的正反馈环促进细胞生长，其中释放的 LTB4 参与 FAS 的上调。因此，我们的发现为 HBxDelta127 介导的细胞生长促进机制提供了新的见解。
