Fukuda Makoto, Longnecker Richard
Department of Microbiology-Immunology, Northwestern University Medical School, 303 E. Chicago Ave., Chicago, IL 60611, USA.
J Virol. 2007 Sep;81(17):9299-306. doi: 10.1128/JVI.00537-07. Epub 2007 Jun 20.
Epstein-Barr virus (EBV) latent membrane protein 2A (LMP2A) is widely expressed in EBV-infected cells within the infected human host and EBV-associated malignancies, suggesting that LMP2A is important for EBV latency, persistence, and EBV-associated tumorigenesis. Previously, we demonstrated that LMP2A provides an antiapoptotic signal through the activation of phosphatidylinositol 3-kinase (PI3-K)/Akt pathway in vitro. However, the exact function of LMP2A in tumor progression is not well understood. In this study, we found that LMP2A did not induce anchorage-independent cell growth in a human keratinocyte cell line, HaCaT, but did in a human gastric carcinoma cell line, HSC-39. In addition, LMP2A activated the PI3-K/Akt pathway in both HaCaT and HSC-39 cells; however, LMP2A did not activate Ras in HaCaT cells but did in HSC-39 cells. Furthermore, the Ras inhibitors manumycin A and a dominant-negative form of Ras (RasN17) and the PI3-K inhibitor LY294002 blocked LMP2A-mediated Akt phosphorylation and anchorage-independent cell growth in HSC-39 cells. These results suggest that constitutive activation of the Ras/PI3-K/Akt pathway by LMP2A is a key factor for LMP2A-mediated transformation.
爱泼斯坦-巴尔病毒（EBV）潜伏膜蛋白2A（LMP2A）在受感染人类宿主内的EBV感染细胞以及EBV相关恶性肿瘤中广泛表达，这表明LMP2A对于EBV潜伏、持续存在以及EBV相关的肿瘤发生很重要。此前，我们在体外证明LMP2A通过激活磷脂酰肌醇3激酶（PI3-K）/Akt途径提供抗凋亡信号。然而，LMP2A在肿瘤进展中的确切功能尚未完全了解。在本研究中，我们发现LMP2A在人角质形成细胞系HaCaT中不诱导非锚定依赖性细胞生长，但在人胃癌细胞系HSC-39中却能诱导。此外，LMP2A在HaCaT和HSC-39细胞中均激活PI3-K/Akt途径；然而，LMP2A在HaCaT细胞中不激活Ras，但在HSC-39细胞中能激活。此外，Ras抑制剂番红霉素A和Ras的显性负性形式（RasN17）以及PI3-K抑制剂LY294002可阻断LMP2A介导的HSC-39细胞中Akt磷酸化和非锚定依赖性细胞生长。这些结果表明，LMP2A对Ras/PI3-K/Akt途径的组成性激活是LMP2A介导的细胞转化的关键因素。
