一項(xiàng)新研究顯示,，病毒可能通過使更多正常細(xì)胞死亡的同時(shí)促進(jìn)有癌癥特征的細(xì)胞生長來誘使癌癥發(fā)生,。病毒可能充當(dāng)了自然選擇的作用：清除幫助病毒復(fù)制的正常細(xì)胞，而保留那些存在所需缺陷的細(xì)胞,。
作者表示,，當(dāng)以上過程不斷發(fā)生時(shí)癌癥就會發(fā)生,。研究負(fù)責(zé)人是來自Pittsburgh大學(xué)醫(yī)學(xué)院的教授Preet M. Chaudhary，結(jié)果發(fā)表在10月24日的《公共科學(xué)圖書館·綜合》（PLoS ONE）上,。
病毒感染和多種癌癥有關(guān),，其中包括多種Hodgkin’s或非Hodgkin’s淋巴瘤、惡性肉瘤,、咽喉和肝臟癌癥,。在過去的數(shù)年中，科學(xué)家提出了很多解釋這一現(xiàn)象的機(jī)制,。其中最常被接受的觀點(diǎn)是：當(dāng)病毒感染細(xì)胞后,，其基因物質(zhì)會對細(xì)胞造成改變，使其生長不受控制,，并最終形成腫瘤,。科學(xué)家還認(rèn)為某些病毒通過慢性炎癥促進(jìn)癌癥發(fā)生,。而Chaudhary博士提出病毒同樣可通過非直接方式導(dǎo)致癌癥,。
Chaudhary說：“我們相信一種分離機(jī)制使被病毒感染的細(xì)胞選擇已存在的變異細(xì)胞群，促進(jìn)其進(jìn)一步生長和復(fù)制,，最終形成完全癌變的細(xì)胞,。結(jié)果類似進(jìn)化中的自然選擇，過度的細(xì)胞死亡或許是驅(qū)動最初癌癥形成的力量,?！盋haudhary將這一模型命名為Phoenix Paradigm，因?yàn)槔碚撋习┌Y產(chǎn)生于死去細(xì)胞的殘留上,。
研究結(jié)果主要來自對感染了卡波西肉瘤皰疹病毒（KSHV）的細(xì)胞研究,，KSHV也被稱為人類皰疹病毒8（HHV-8）?？茖W(xué)家分析了和癌癥發(fā)展相關(guān)的K13基因,。K13表達(dá)程度較低的細(xì)胞允許KSHV復(fù)制，科學(xué)家注意到這些細(xì)胞最終死去,。而K13高度表達(dá)的細(xì)胞在KSHV復(fù)制后出現(xiàn),，并且表現(xiàn)出促進(jìn)癌癥的兩個(gè)關(guān)鍵蛋白的表達(dá)缺陷。
Chaudhary說：“一旦得到進(jìn)一步證實(shí),，這一模型不但能促進(jìn)我們對癌癥過程的了解,，還能發(fā)展有效的預(yù)防和治療手段?！?（教育部科技發(fā)展中心）
原文鏈接：http://www.physorg.com/news112424683.html
原始出處:
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.
