Interferon-induced SLFNs and tumorigenesis

说明(申请人提供)：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，是预防癌症和病毒感染的免疫监测的关键要素。虽然已经鉴定了几种干扰素刺激基因(ISGs)，它们介导了IFN的抗病毒特性，但对于介导IFN抗增殖和抗肿瘤作用的基因和蛋白产物却知之甚少。我们发现了一个新的ISGs家族，即SLFN基因家族。我们的研究首次证明了I型干扰素受体(IFNR)的参与导致了小鼠和人类SLFN基因的表达，并证明该家族的成员参与了抑制非锚定非依赖性恶性细胞生长和抑制黑色素瘤细胞的胶原侵袭。目前的建议是一种系统的方法，以确定不同的SLFN基因在抑制肿瘤发生和IFN的抗肿瘤作用中的作用；并检查特定SLFN的表达缺陷是否与体内和体外的干扰素耐药相关。具体目标1将定义SLFN表达的调节机制，并将剖析不同的SLFN在干扰素诱导的生长抑制效应中的功能作用。还将进行研究，以确定SLFN下游反应的效应物和中介物。特异性目标2将决定诱导SLFN蛋白的表达是否对产生干扰素的抗肿瘤作用是必要的？在体内建立实体瘤小鼠模型。为此，将使用具有Elektra表型(Slfn2eka/Eka)的小鼠或SLfn1或Slfn3基因敲除小鼠建立恶性黑色素瘤或肾细胞癌(RCC)小鼠模型。最后，特殊目标3将检查人类SLFN的缺陷表达是否与恶性黑色素瘤或肾细胞癌(RCC)患者的原代恶性细胞对IFN1抗肿瘤特性的抵抗有关，RCC是已知对免疫调节和干扰素治疗有反应的恶性肿瘤。总之，拟议的研究将解决关于SLFN在产生抗肿瘤反应中的作用以及恶性肿瘤细胞通过何种方式对IFN产生耐药性的重要问题。 公共卫生相关性：干扰素(IFN)在抗癌免疫监测中发挥关键作用，并在某些临床环境中具有重要活动，但它们产生效果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)，它们调节细胞周期进程并介导干扰素依赖的生长抑制反应。目前的提议将准确地定义这些基因及其蛋白产物在体内和体外产生IFN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对干扰素针对恶性黑色素瘤和肾癌的抗肿瘤作用的抵抗有关。

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.