一项新研究显示，病毒可能通过使更多正常细胞死亡的同时促进有癌症特征的细胞生长来诱使癌症发生。病毒可能充当了自然选择的作用：清除帮助病毒复制的正常细胞，而保留那些存在所需缺陷的细胞。
作者表示，当以上过程不断发生时癌症就会发生。研究负责人是来自Pittsburgh大学医学院的教授Preet M. Chaudhary，结果发表在10月24日的《公共科学图书馆·综合》（PLoS ONE）上。
病毒感染和多种癌症有关，其中包括多种Hodgkin’s或非Hodgkin’s淋巴瘤、恶性肉瘤、咽喉和肝脏癌症。在过去的数年中，科学家提出了很多解释这一现象的机制。其中最常被接受的观点是：当病毒感染细胞后，其基因物质会对细胞造成改变，使其生长不受控制，并最终形成肿瘤。科学家还认为某些病毒通过慢性炎症促进癌症发生。而Chaudhary博士提出病毒同样可通过非直接方式导致癌症。
Chaudhary说：“我们相信一种分离机制使被病毒感染的细胞选择已存在的变异细胞群，促进其进一步生长和复制，最终形成完全癌变的细胞。结果类似进化中的自然选择，过度的细胞死亡或许是驱动最初癌症形成的力量。”Chaudhary将这一模型命名为Phoenix Paradigm，因为理论上癌症产生于死去细胞的残留上。
研究结果主要来自对感染了卡波西肉瘤疱疹病毒（KSHV）的细胞研究，KSHV也被称为人类疱疹病毒8（HHV-8）。科学家分析了和癌症发展相关的K13基因。K13表达程度较低的细胞允许KSHV复制，科学家注意到这些细胞最终死去。而K13高度表达的细胞在KSHV复制后出现，并且表现出促进癌症的两个关键蛋白的表达缺陷。
Chaudhary说：“一旦得到进一步证实，这一模型不但能促进我们对癌症过程的了解，还能发展有效的预防和治疗手段。” （教育部科技发展中心）
原文链接：http://www.physorg.com/news112424683.html
原始出处:
PLoS ONE
Received: August 15, 2007; Accepted: October 4, 2007; Published: October 24, 2007
K13 Blocks KSHV Lytic Replication and Deregulates vIL6 and hIL6 Expression: A Model of Lytic Replication Induced Clonal Selection in Viral Oncogenesis
Jinshun Zhao1#, Vasu Punj1#, Hittu Matta1#, Lucia Mazzacurati1, Sandra Schamus1, Yanqiang Yang1, Tianbing Yang2, Yan Hong1, Preet M. Chaudhary1*
1 Division of Hematology-Oncology, Department of Medicine, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America, 2 Spang Translational Research Core Facility, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
Abstract
Background
Accumulating evidence suggests that dysregulated expression of lytic genes plays an important role in KSHV (Kaposi's sarcoma associated herpesvirus) tumorigenesis. However, the molecular events leading to the dysregulation of KSHV lytic gene expression program are incompletely understood.
Methodology/Principal Findings
We have studied the effect of KSHV-encoded latent protein vFLIP K13, a potent activator of the NF-κB pathway, on lytic reactivation of the virus. We demonstrate that K13 antagonizes RTA, the KSHV lytic-regulator, and effectively blocks the expression of lytic proteins, production of infectious virions and death of the infected cells. Induction of lytic replication selects for clones with increased K13 expression and NF-κB activity, while siRNA-mediated silencing of K13 induces the expression of lytic genes. However, the suppressive effect of K13 on RTA-induced lytic genes is not uniform and it fails to block RTA-induced viral IL6 secretion and cooperates with RTA to enhance cellular IL-6 production, thereby dysregulating the lytic gene expression program.
Conclusions/Significance
Our results support a model in which ongoing KSHV lytic replication selects for clones with progressively higher levels of K13 expression and NF-κB activity, which in turn drive KSHV tumorigenesis by not only directly stimulating cellular survival and proliferation, but also indirectly by dysregulating the viral lytic gene program and allowing non-lytic production of growth-promoting viral and cellular genes. Lytic Replication-Induced Clonal Selection (LyRICS) may represent a general mechanism in viral oncogenesis.
Figure 1. K13 blocks lytic replication in BCBL1-TREx-RTA cells
A. Expression of K13-ERTAM in BCBL1-TREx-RTA cells as determined by immunoblotting with a Flag antibody. B–C. Treatment with 4OHT induces nuclear translocation (B) and DNA-binding (C) of p65 in BCBL1-TREx-RTA cells expressing K13-ERTAM but is without effect in the control cells. Nuclear translocation was measured by indirect immunofluorescence analysis using a p65/RelA primary antibody (Santa Cruz Biotechnology). D. Inhibition of TPA-induced K8.1 and ORF59 expression by K13. BCBL1-TREx-RTA cells expressing an empty vector and K13-ERTAM, respectively, were left untreated or pretreated with 4OHT for 18 h and then induced with TPA for 96 h. K8.1 and ORF59 expression was detected by indirect immunofluorescence analysis with the indicated antibodies and revealed by Alexa-488-conjugated secondary antibodies. Nuclei were counterstained with Hoechst 33342. Cells were imaged with an Olympus Fluorescent microscope equipped with a SPOT camera. A representative of two independent experiments is shown.
