在20世紀(jì)80年代,，Harald zur Hausen和他的同事就發(fā)現(xiàn)特殊類型的人類乳突瘤病毒（HPV）會引起子宮頸癌?？茖W(xué)家很快就發(fā)現(xiàn)這些病原體導(dǎo)致細(xì)胞惡化的機(jī)制?，F(xiàn)在科學(xué)家已經(jīng)知道，這其中的罪魁禍?zhǔn)资遣《镜鞍譋6和E7,。這兩種蛋白會關(guān)閉不同的細(xì)胞調(diào)控功能,，從而刺激細(xì)胞生長。
在這項研究中,，F(xiàn)rank Rösl教授和他的同事識別了高風(fēng)險HPV16的E6腫瘤蛋白激發(fā)癌變的另一個機(jī)制,。該致癌基因沉默了一種叫干擾素卡帕（interferon-kappa）的免疫蛋白的產(chǎn)生。干擾素是我們免疫系統(tǒng)中的蛋白,，能夠刺激機(jī)體對病毒和腫瘤產(chǎn)生免疫應(yīng)答,，其由白細(xì)胞和其他類型的細(xì)胞產(chǎn)生。干擾素卡帕與HPV感染有關(guān),，因為它主要是在皮膚和黏膜的細(xì)胞中產(chǎn)生,。如果干擾素卡帕不能對細(xì)胞起作用，那么免疫防御中的其他蛋白同樣會停止執(zhí)行正確的功能,。
研究人員首次證實,，HPV16能通過DNA的生化修飾關(guān)閉干擾素卡帕基因。那些對遺傳物質(zhì)的修飾叫后天突變,。在培養(yǎng)皿中,，研究人員觀察了HPV感染細(xì)胞的過程，發(fā)現(xiàn)干擾素卡帕表現(xiàn)出沉默,。他們隨后在子宮頸癌樣本中證實了這項研究結(jié)果,。
干擾素卡帕是天然免疫應(yīng)答的重要部分，該古老的進(jìn)化防御機(jī)制能夠使機(jī)體在被致病原感染后立即產(chǎn)生防御,。通過關(guān)閉干擾素產(chǎn)生,，病毒能保護(hù)受感染的細(xì)胞被免疫應(yīng)答破壞。病毒的這一策略能導(dǎo)致癌癥發(fā)生,。
接下來研究人員將關(guān)注于是否控制干擾素卡帕能夠減緩子宮頸癌細(xì)胞的生長,，這或許有助于該疾病的治療。（生物谷Bioon.com）
生物谷推薦原始出處：
Cancer Research 69, 8718, November 15, 2009.doi: 10.1158/0008-5472.CAN-09-0550
Epigenetic Silencing of Interferon-κ in Human Papillomavirus Type 16–Positive Cells
Bladimiro Rincon-Orozco1, Gordana Halec2, Simone Rosenberger1, Dorothea Muschik1, Ingo Nindl1, Anastasia Bachmann3, Tina Maria Ritter1, Bolormaa Dondog4, Regina Ly1, Franz X. Bosch2, Rainer Zawatzky1 and Frank R?sl1
1 Angewandte Tumorvirologie, Abteilung Virale Transformationsmechanismen, Deutsches Krebsforschungszentrum, Universit?t Heidelberg; 2 Molekularbiologisches Labor, Universit?ts-HNO-Klinik Heidelberg; 3 Molecular Alcohol Research in Gastroenterology, Universit?t Heidelberg; and 4 Angewandte Tumorvirologie, Abteilung Genomver?nderungen und Karzinogenese, Deutsches Krebsforschungszentrum, Heidelberg, Germany
We have investigated interferon-κ (IFN-κ) regulation in the context of human papillomavirus (HPV)–induced carcinogenesis using primary human foreskin keratinocytes (HFK), immortalized HFKs encoding individual oncoproteins of HPV16 (E6, E7, and E6/E7), and cervical carcinoma cells. Here, IFN-κ was suppressed in the presence of E6, whereas its expression was not affected in HFKs or E7-immortalized HFKs. Transcription could be reactivated after DNA demethylation but was decreased again upon drug removal. Partial reactivation could also be accomplished when E6 was knocked down, suggesting a contribution of E6 in IFN-κ de novo methylation. We identified a single CpG island near the transcriptional start site as being involved in selective IFN-κ expression. To prove the functional relevance of IFN- in building up an antiviral response, IFN-κ was ectopically expressed in cervical carcinoma cells where protection against vesicular stomatitis virus–mediated cytolysis could be achieved. Reconstitution of IFN-κ was accompanied by an increase of p53, MxA, and IFN-regulatory factors, which was reversed by knocking down either IFN-κ or p53 by small interfering RNA. This suggests the existence of a positive feedback loop between IFN-κ, p53, and components of IFN signaling pathway to maintain an antiviral state. Our in vitro findings were further corroborated in biopsy samples of cervical cancer patients, in which IFN-κ was also downregulated when compared with normal donor tissue. This is the first report showing an epigenetic silencing of type I IFN after HPV16 oncogene expression and revealing a novel strategy on how high-risk HPVs can abolish the innate immune response in their genuine host cells.
