Wakisaka Naohiro, Pagano Joseph S
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599-7295, USA.
Anticancer Res. 2003 May-Jun;23(3A):2133-8.
The oncogenic properties of the principal EBV oncoprotein, Latent Membrane Protein 1 (LMP-1), include the ability to induce invasiveness and metastasis factors. We have shown that LMP-1 induces matrix metalloproteinase 9 (MMP-9), a type IV collagenase that disrupts basement membrane. Also, cyclooxygenase-2 (COX-2), which is overexpressed in diverse malignancies, is induced by LMP-1; the enzyme is functional, and co-expressed with LMP-1 in NPC. Inhibitors of the NF kappa B signaling pathway, which is activated by LMP-1, including I kappa B super-repressor and aspirin reduce or cancel induction of MMP-9, COX-2 and invasiveness of LMP-1-expressing cells. Production of VEGF, also induced by LMP-1, is decreased by a COX-2-specific inhibitor. We now show that LMP-1 induces expression of the angiogenic Fibroblast Growth Factor-2 (FGF-2). Furthermore, LMP-1 also causes secretion of the 18 kDa isoform of this protein--a newly identified function for LMP-1. Secretion of FGF-2 is independently signaled through the NF-kappa B pathway. Release of the protein is not dependent on the classical ER/Golgi secretory pathway, but secretion of FGF-2 is suppressed by ouabain, an inhibitor of the Na+/K(+)-ATPase alpha 1 subunit. Finally LMP-1 induces expression of Hypoxia-Inducible Factor-1 alpha (HIF-1 alpha), which mediates adaptation of cells to O2-depleted states. Thus LMP-1 is not only directly oncogenic, it can induce a constellation of factors that reveal the additional role of EBV in invasive cancers such as NPC. Alteration of cellular phenotype independent of transforming effects may be a property of other tumor viruses.
EBV主要致癌蛋白潜伏膜蛋白1（LMP-1）的致癌特性包括诱导侵袭和转移因子的能力。我们已经证明，LMP-1可诱导基质金属蛋白酶9（MMP-9），这是一种能破坏基底膜的IV型胶原酶。此外，LMP-1可诱导在多种恶性肿瘤中过表达的环氧合酶-2（COX-2）；该酶具有功能，并在鼻咽癌中与LMP-1共同表达。由LMP-1激活的NF-κB信号通路的抑制剂，包括IκB超级抑制因子和阿司匹林，可减少或消除MMP-9、COX-2的诱导以及LMP-1表达细胞的侵袭性。LMP-1诱导产生的血管内皮生长因子（VEGF），可被COX-2特异性抑制剂降低。我们现在表明，LMP-1可诱导血管生成性成纤维细胞生长因子2（FGF-2）的表达。此外，LMP-1还能促使该蛋白18 kDa异构体的分泌——这是LMP-1新发现的功能。FGF-2的分泌通过NF-κB信号通路独立发出信号。该蛋白的释放不依赖于经典的内质网/高尔基体分泌途径，但FGF-2的分泌可被钠钾ATP酶α1亚基的抑制剂哇巴因抑制。最后，LMP-1可诱导缺氧诱导因子-1α（HIF-1α）的表达，该因子介导细胞对缺氧状态的适应。因此，LMP-1不仅直接致癌，还能诱导一系列因子，揭示EBV在鼻咽癌等侵袭性癌症中的额外作用。独立于转化作用的细胞表型改变可能是其他肿瘤病毒的特性。
