Interferon-induced SLFNs and tumorigenesis

描述（由申请方提供）：I型干扰素（IFN）是具有重要抗肿瘤和抗病毒活性的多效性细胞因子，并构成针对癌症和病毒感染的免疫监视的关键要素。虽然已经鉴定了介导IFN的抗病毒特性的几种干扰素刺激基因（ISG），但是对介导IFN的抗增殖和抗病毒作用的产生的基因和蛋白质产物知之甚少。我们已经确定了一个新的家庭ISGs，家庭SLFN基因。我们的数据提供了第一个证据表明，参与的I型IFN受体（IFNR）的结果在小鼠和人SLFN基因的表达，并已证明，该家族的成员参与抑制锚定非依赖性恶性细胞生长和抑制胶原蛋白的黑色素瘤细胞的侵袭。目前的建议是一个系统的方法来定义不同的SLFN基因的作用，在抑制肿瘤发生和干扰素的干扰作用的产生，并检查是否在特定的SLFN的表达缺陷与干扰素抗性在体外和体内。具体目标1将定义SLFN表达的调节机制，并将剖析不同SLFN在IFN诱导的生长抑制作用中的功能作用。还将进行研究，以确定SLFN下游反应的效应子和介质。具体目标2将确定是否诱导表达SLFN蛋白是必不可少的产生干扰素的抗肿瘤作用？在体内实体瘤小鼠模型中。为此，将使用具有elektra表型的小鼠（Slfn 2 eka/eka）或Slfn 1或Slfn 3敲除小鼠建立恶性黑素瘤或肾细胞癌（RCC）小鼠模型。最后，具体目标3将检查人SLFN的缺陷性表达是否与来自恶性黑素瘤或肾细胞癌（RCC）患者的原发性恶性细胞上对IFN 1的抗肿瘤特性的抗性相关，所述恶性肿瘤已知对免疫调节和IFN治疗有反应。总而言之，拟议的研究将解决SLFN在产生抗肿瘤反应中的作用以及恶性细胞对IFN产生耐药性的方法等重要问题。 公共卫生相关性：干扰素（IFN）在癌症的免疫监视中起着关键作用，并在某些临床环境中具有重要的活性，但它们产生作用的确切机制仍有待确定。我们已经确定了一组新的ISGs（SLFN基因），调节细胞周期进程和介导IFN依赖性生长抑制反应。目前的建议将精确地定义这些基因和它们的蛋白质产物在体外和体内产生IFN的抗肿瘤特性中的作用。它还将确定这些基因的缺陷表达是否与IFN对恶性黑色素瘤和肾细胞癌的抗肿瘤作用的抗性相关。

DESCRIPTION (provided by applicant): Type I interferons (IFNs) are pleiotropic cytokines with important antineoplastic and antiviral activities and constitute key elements in the immune surveillance against cancer and viral infections. Although several interferon stimulated genes (ISGs) that mediate the antiviral properties of IFNs have been identified, very little is known on the genes and protein products that mediate generation of the antiproliferative and antineoplastic effects of IFNs. We have identified a novel family of ISGs, the family of SLFN genes. Our data have provided the first evidence that engagement of the Type I IFN receptor (IFNR) results in expression of mouse and human SLFN genes, and have demonstrated that members of this family are involved in the suppression of anchorage-independent malignant cell growth and inhibition of collagen invasion by melanoma cells. The current proposal is a systematic approach to define the roles of distinct SLFN genes in suppression of oncogenesis and in the generation of the antineoplastic effects of IFNs; and to examine whether defects in the expression of specific SLFNs correlates with IFN-resistance in vitro and in vivo. Specific aim 1 will define the mechanisms of regulation of expression of SLFNs and will dissect the functional roles of distinct SLFNs in IFN-induced growth inhibitory effects. Studies to define effectors and mediators of responses downstream of SLFNs will be also performed. Specific aim 2 will determine whether induction of expression of SLFN proteins is essential for generation of the antineoplastic effects of IFN? in solid tumor mouse models in vivo. For that purpose malignant melanoma or renal cell carcinoma (RCC) mouse models will be established using mice with the elektra phenotype (Slfn2eka/eka) or Slfn1 or Slfn3 knockout mice. Finally, specific aim 3 will examine whether defective expression of human SLFNs correlates with resistance to the antineoplastic properties of IFN1 on primary malignant cells from patients with malignant melanoma or renal cell carcinoma (RCC), malignancies known to be responsive to immune modulation and IFN-treatment. Altogether, the proposed studies will address important issues on the role of SLFNs in the generation of antitumor responses and the means by which malignant cells develop resistance to IFNs. PUBLIC HEALTH RELEVANCE: Interferons (IFNs) play key roles in the immune surveillance against cancer and have important activities in certain clinical settings, but the precise mechanisms by which they generate their effects remain to be defined. We have identified a novel group of ISGs (SLFN genes) that regulate cell cycle progression and mediate IFN-dependent growth inhibitory responses. The current proposal will precisely define the role of these genes and their protein products in the generation of the antitumor properties of IFNs in vitro and in vivo. It will also determine whether defective expression of these genes correlates with resistance to the antitumor effects of IFNs against malignant melanoma and renal cell carcinoma.