Miura Tanya A, Cook James L, Potter Terence A, Ryan Sharon, Routes John M
Department of Microbiology, University of Colorado Health Sciences Center, Aurora, CO, USA.
J Cell Biochem. 2007 Mar 1;100(4):929-40. doi: 10.1002/jcb.21057.
The use of adenovirus serotype 2 or 5 (Ad2/5) E1A as therapy for human malignancy requires an understanding of the mechanisms involved in E1A-induced tumor suppression. The prevailing use of E1A in the treatment of human malignancy stresses the non-immunologically mediated, anti-tumorigenic activities of E1A. However, the capacity of E1A to elicit a NK-cell and T-cell anti-tumor immune response and to sensitize tumor cells to lysis by immune effector molecules utilized by NK cells and T cells is also an important component of the anti-tumorigenic activity of E1A. This immune-mediated anti-tumorigenic activity of E1A is not shared by functionally similar viral oncoproteins such as the human papillomavirus type 16 (HPV16) E7 oncoprotein and is dependent on the capacity of E1A to interact with transcriptional coadapter, p300. To further define the molecular mechanisms whereby E1A reduces tumorigenicity, we compared total cellular gene expression in H4 cells, a human fibrosarcoma cell line, to gene expression in H4 cells stably expressing E1A, E7, or mutant forms of E1A that do not bind p300. The expression of E1A, but not E7, in H4 cells modulated the expression of cellular genes that may promote apoptosis, enhance immunogenicity and reduce tumor cell metastasis. The difference in the ability of E1A and E7 to modulate the expression of cellular genes that may influence tumorigenicity was largely attributable to distinct interactions of E1A and E7 with p300. Results of this study will be useful in designing novel strategies to augment the anti-tumorigenic activities of E1A.
使用2型或5型腺病毒（Ad2/5）E1A治疗人类恶性肿瘤需要了解E1A诱导肿瘤抑制所涉及的机制。E1A在人类恶性肿瘤治疗中的普遍应用强调了其非免疫介导的抗肿瘤活性。然而，E1A引发自然杀伤细胞（NK细胞）和T细胞抗肿瘤免疫反应以及使肿瘤细胞对NK细胞和T细胞利用的免疫效应分子介导的裂解敏感的能力，也是E1A抗肿瘤活性的重要组成部分。E1A的这种免疫介导的抗肿瘤活性并非功能相似的病毒癌蛋白（如16型人乳头瘤病毒（HPV16）E7癌蛋白）所共有，并且依赖于E1A与转录共激活因子p300相互作用的能力。为了进一步明确E1A降低致瘤性的分子机制，我们比较了人纤维肉瘤细胞系H4细胞中的总细胞基因表达与稳定表达E1A、E7或不与p300结合的E1A突变形式的H4细胞中的基因表达。H4细胞中E1A而非E7的表达调节了可能促进细胞凋亡、增强免疫原性并减少肿瘤细胞转移的细胞基因的表达。E1A和E7调节可能影响致瘤性的细胞基因表达的能力差异很大程度上归因于E1A和E7与p300的不同相互作用。本研究结果将有助于设计增强E1A抗肿瘤活性的新策略。
