Interferon-induced SLFNs and tumorigenesis

描述（由申请人提供）：I型干扰素（ifn）是一种多效细胞因子，具有重要的抗肿瘤和抗病毒活性，是对抗癌症和病毒感染的免疫监视的关键因素。虽然已经确定了几种介导ifn抗病毒特性的干扰素刺激基因（isg），但对介导ifn抗增殖和抗肿瘤作用的基因和蛋白产物知之甚少。我们已经确定了一个新的isg家族，SLFN基因家族。我们的数据提供了第一个证据，证明I型IFN受体（IFNR）的参与导致小鼠和人类SLFN基因的表达，并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黑色素瘤细胞的胶原侵袭。目前的建议是一种系统的方法来定义不同的SLFN基因在抑制肿瘤发生和ifn抗肿瘤作用的产生中的作用；研究特异性SLFNs的表达缺陷是否与体外和体内的ifn耐药相关。具体目的1将定义SLFNs表达的调控机制，并剖析不同SLFNs在ifn诱导的生长抑制作用中的功能作用。研究还将确定SLFNs下游反应的效应物和介质。特异性目的2将确定诱导SLFN蛋白的表达是否对IFN抗肿瘤作用的产生至关重要？实体瘤小鼠体内模型。为此，将使用elektra表型（Slfn2eka/eka）或Slfn1或Slfn3敲除小鼠建立恶性黑色素瘤或肾细胞癌（RCC）小鼠模型。最后，特异性目的3将研究人类SLFNs的缺陷表达是否与恶性黑色素瘤或肾细胞癌（RCC）患者原发性恶性细胞对IFN1抗肿瘤特性的耐药性相关，这些恶性肿瘤已知对免疫调节和ifn治疗有反应。总之，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产生耐药性的途径等重要问题。

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.