Hu G, Liu W, Hanania E G, Fu S, Wang T, Deisseroth A B
Department of Hematology, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Cancer Gene Ther. 1995 Mar;2(1):19-32.
Human cervical carcinoma cell lines that harbor human papilloma virus (HPV) have been reported to express HPV E6 and E7 proteins at least in the beginning stages if not at all stages of the disease. The HPV E6 and E7 proteins bind to and inactivate the products of the p53 and retinoblastoma (Rb) tumor suppressor genes, which thereby allow the cervical carcinoma cells to circumvent the action of these tumor suppressor genes. We observed that the introduction of the antisense HPV 18 E6 and E7 sequences, as well as a sense cDNA for the human wild-type Rb gene into a human cervical carcinoma cell line (HeLa), which is positive for the HPV 18 provirus, decreased the in vitro and in vivo growth rate of the transfected cells if both antisense transcripts for the HPV 18 E6 and E7 and sense transcripts for human Rb were expressed. In addition, overexpression of a complementary DNA (cDNA) for the Rb messenger RNA was sufficient to slow the proliferation of HeLa cells, and the level of Rb cDNA expression was correlated with the degree to which the rate of growth of the tumor was slowed. The results of our experiments show that the presence of HPV E6 and E7 proteins and the resultant inactivation of Rb in cervical carcinoma cells contributes to the neoplastic phenotype even in highly evolved cervical carcinoma cell lines such as HeLa, which have been derived from a cervical carcinoma patient at an advanced stage of the disease process. These data suggest that the HPV proteins play a role not only at the beginning of cervical cancer, but also at advanced stages of this disease. These experiments may lead to genetic approaches to the control of this disease that involve antisense sequences that downregulate the E6 and E7 genes or lead to expression of the Rb gene.
据报道，携带人乳头瘤病毒（HPV）的人宫颈癌细胞系至少在疾病的初始阶段（即便不是所有阶段）都会表达HPV E6和E7蛋白。HPV E6和E7蛋白会结合并使p53和视网膜母细胞瘤（Rb）肿瘤抑制基因的产物失活，从而使宫颈癌细胞能够规避这些肿瘤抑制基因的作用。我们观察到，将反义HPV 18 E6和E7序列以及人野生型Rb基因的正义cDNA导入一个HPV 18前病毒呈阳性的人宫颈癌细胞系（HeLa）中，如果HPV 18 E6和E7的反义转录本以及人Rb的正义转录本都得以表达，那么转染细胞的体外和体内生长速率都会降低。此外，Rb信使RNA的互补DNA（cDNA）的过表达足以减缓HeLa细胞的增殖，并且Rb cDNA的表达水平与肿瘤生长速率减缓的程度相关。我们的实验结果表明，即使在像HeLa这样高度进化的宫颈癌细胞系（源自疾病进程晚期的宫颈癌患者）中，HPV E6和E7蛋白的存在以及由此导致的Rb失活也有助于肿瘤表型的形成。这些数据表明，HPV蛋白不仅在宫颈癌的起始阶段起作用，在该疾病的晚期阶段也发挥作用。这些实验可能会带来控制这种疾病的基因方法，这些方法涉及下调E6和E7基因的反义序列或促使Rb基因表达。
