CHARACTERIZATION OF SEMAPHORIN IV IN TUMORIGENESIS

Semaphorin IV 在肿瘤发生中的表征

基本信息

批准号：
6606903
负责人：
CHRISTIN TSE
金额：
$ 4.51万
依托单位：
SAGRES DISCOVERY
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-02-01 至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/6606903
关键词：
DNA methylation apoptosis athymic mouse azacitidine cell line neoplasm /cancer genetics northern blottings nucleic acid repetitive sequence ovary neoplasms polymerase chain reaction small cell lung cancer tumor suppressor genes tumor suppressor proteins vascular endothelial growth factors western blottings

项目摘要

SEMAPHORIN IV (SEMA IV) resides in 3p21.3 on chromosome 3, a region that exhibits a high loss of heterozygosity in several types of cancers, e.g., small cell lung cancer (SCLC) and ovarian cancer. Recently, the laboratory of Dr. Naylor demonstrated that tumor growth was inhibited in mouse fibrosarcoma (A9) cells transfected with SEMA IV as opposed to control A9 cells where tumors formed in an athymic nude mice assay. Furthermore, SEMA IV confers protection from chemotherapeutic drug-induced apoptosis. Thus, SEMA IV appears to be a putative tumor suppressor gene in 3p21.3. By definition, this would indicate that loss of SEMA IV function would result in tumor growth. Over 90 percent of SCLC have loss a region in chromosome 3 overlapping with the SEMA IV locus, however, no mutations have been found in the remaining locus. Another unexplored possibility by which sema iv may be disrupted is by differential DNA methylation. In neuronal development, Sema IV serves as a chemorepellent protein in axonal guidance, eliciting a response through the neuropilin-2 (np-2) receptor. However, its role in tumorigenesis is unknown. Recently, it has been shown that np-2 as well as, neuropilin-1 (np-1) also serve as coreceptors for vascular endothelial growth factor (VEGF165). VEGF165, one of the most potent angiogenic factors, also binds two receptor tyrosine kinases, KDR and flt-1. Np-1 has been shown to increase the affinity of VEGF165 to KDR and its mitogenic activity. Taken together, one action of SEMA IV in tumor suppression may be to competitively inhibit VEGF action. The goal of this proposal is to determine if DNA methylation is involved in the downregulation of SEMA IV gene expression in SCLC and to elucidate the mechanism(s) by which sema iv suppresses tumor formation.

Semaphorin IV（SEMA IV）驻留在3P21.3上，在3P21.3上，该区域在几种类型的癌症中表现出高度杂合性丧失的区域，例如小细胞肺癌（SCLC）和卵巢癌。最近，Naylor博士的实验室表明，用SEMA IV转染的小鼠纤维肉瘤（A9）细胞抑制了肿瘤生长，而不是对照A9细胞，其中在无胸腺裸鼠分析中形成肿瘤。此外，SEMA IV赋予化学治疗性药物诱导的细胞凋亡的保护。因此，在3p21.3中，SEMA IV似乎是推定的肿瘤抑制基因。根据定义，这将表明SEMA IV功能的丧失会导致肿瘤生长。超过90％的SCLC损失了与SEMA IV基因座重叠的3染色体中的一个区域，但是，其余基因座尚未发现突变。 SEMA IV可能被破坏的另一种未经探索的可能性是通过差异DNA甲基化。在神经元发育中，SEMA IV在轴突引导中充当化学蛋白质，通过Neuropilin-2（NP-2）受体引起反应。但是，其在肿瘤发生中的作用尚不清楚。最近，已经表明，NP-2以及Neuropilin-1（NP-1）也充当血管内皮生长因子（VEGF165）的共感受器。 VEGF165是最有效的血管生成因子之一，还结合了两个受体酪氨酸激酶KDR和FLT-1。 NP-1已被证明会增加VEGF165对KDR及其有丝分裂活性的亲和力。综上所述，SEMA IV在肿瘤抑制中的一种作用可能是竞争性抑制VEGF作用。该提案的目的是确定SCLC中SEMA IV基因表达的下调是否涉及DNA甲基化，并阐明SEMA IV抑制肿瘤形成的机制。