在20世纪80年代，Harald zur Hausen和他的同事就发现特殊类型的人类乳突瘤病毒（HPV）会引起子宫颈癌。科学家很快就发现这些病原体导致细胞恶化的机制。现在科学家已经知道，这其中的罪魁祸首是病毒蛋白E6和E7。这两种蛋白会关闭不同的细胞调控功能，从而刺激细胞生长。
在这项研究中，Frank Rösl教授和他的同事识别了高风险HPV16的E6肿瘤蛋白激发癌变的另一个机制。该致癌基因沉默了一种叫干扰素卡帕（interferon-kappa）的免疫蛋白的产生。干扰素是我们免疫系统中的蛋白，能够刺激机体对病毒和肿瘤产生免疫应答，其由白细胞和其他类型的细胞产生。干扰素卡帕与HPV感染有关，因为它主要是在皮肤和黏膜的细胞中产生。如果干扰素卡帕不能对细胞起作用，那么免疫防御中的其他蛋白同样会停止执行正确的功能。
研究人员首次证实，HPV16能通过DNA的生化修饰关闭干扰素卡帕基因。那些对遗传物质的修饰叫后天突变。在培养皿中，研究人员观察了HPV感染细胞的过程，发现干扰素卡帕表现出沉默。他们随后在子宫颈癌样本中证实了这项研究结果。
干扰素卡帕是天然免疫应答的重要部分，该古老的进化防御机制能够使机体在被致病原感染后立即产生防御。通过关闭干扰素产生，病毒能保护受感染的细胞被免疫应答破坏。病毒的这一策略能导致癌症发生。
接下来研究人员将关注于是否控制干扰素卡帕能够减缓子宫颈癌细胞的生长，这或许有助于该疾病的治疗。（生物谷Bioon.com）
生物谷推荐原始出处：
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.
