Suppression of Melanoma Initiation and Progression by NM23-H1

NM23-H1 抑制黑色素瘤的发生和进展

基本信息

批准号：
8686773
负责人：
David M Kaetzel
金额：
$ 36.13万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-10 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8686773
关键词：
Ablation Automobile Driving Beds Biological Models Cell Culture Techniques Cell Line Collaborations Cultured Tumor Cells Cutaneous Melanoma DNA DNA Repair DNA Repair Pathway Development Diagnosis Disease Distant Double Strand Break Repair Exhibits Exposure to Female Gene Expression Gene Mutation Gene Silencing Genes Genomics Growth Factor Hepatocyte Growth Factor Homologous Gene Hybrids In Vitro Incidence Individual Lesion Malignant - descriptor Malignant Neoplasms Massive Parallel Sequencing Mediating Metastasis Suppressor Genes Metastatic Melanoma Metastatic to Modeling Molecular Molecular Profiling Mouse Strains Mus Mutagenesis Mutation NME1 gene Neoplasm Metastasis Nucleoside Diphosphate Kinase A Nucleotide Excision Repair Organ Pathway interactions Patients Phosphodiesterase I Precancerous melanosis Process Protein Isoforms Proteins Radiation Induced DNA Damage Relative (related person)Repair Complex Risk Factors Role Signal Pathway Skin Cancer Skin tanning Staging Survival Rate Technology Testing Therapeutic Time Transgenic Mice UV-induced melanoma Ultraviolet Rays Work Yang cancer cell cancer therapy combat conventional therapy effective therapy experience genome sequencing improved insight melanoma mouse model new therapeutic target novel novel diagnostics novel therapeutic intervention outcome forecast prognostic protein expression protein function repaired success transcriptome sequencing tumor growth

项目摘要

DESCRIPTION (provided by applicant): Cutaneous malignant melanoma (CMM) is the most lethal form of skin cancer, and its incidence has been increasing at an alarming rate in the U.S. and around the world. Exposure to damaging ultraviolet radiation (UVR) is clearly a risk factor for the disease, borne out by the recent linkage between tanning bed usage and dramatically increased melanoma incidence in young females. Better understanding of the mechanisms by which CMM progresses to metastatic forms is likely to provide important new therapeutic approaches for improving survival rates. The study of metastasis suppressor genes, such as NM23-H1 (NM23-M1 in mouse), has provided new insights into molecular mechanisms underlying melanoma metastasis. This application builds on our novel observations that NM23-H1 is a 3'-5' exonuclease which exerts proofreading activity on DNA in vitro, that its 3'-5' exonuclease activity is required for metastasis suppressor function, and that the protein promotes repair of UVR-induced lesions in DNA. In addition, transgenic mouse models developed for this project recapitulate for the first time the metastasis suppressor function of NM23-H1 in UVR-induced CMM. Our findings support a model in which loss of NM23-H1 expression results in compromised genomic integrity and mutations that drive malignant progression in CMM. In Specific Aim 1, the contributions of NM23-M1 and NM23-M2 to UV radiation-induced metastatic melanoma will be determined in transgenic mouse strains deficient in expression of one, or both, of the isoforms. In Specific Aim 2, the molecular mechanisms underlying promotion of DNA repair pathways by NM23 proteins will be elucidated, and the impact of perturbing those pathways on metastasis suppressor activity assessed in cell culture and tumor cell explanation model systems. Specific Aim 3 will apply the powerful technologies of massively parallel sequencing for whole genome sequencing and RNA-seq to primary and metastatic melanomas to identify candidate metastasis-driving genomic alterations and gene expression profiles. The proposed studies will provide the first systematic analysis of specific DNA repair and related pathways through which a metastasis suppressor gene opposes malignant progression, as well as the first application of a transgenic mouse model to the study of metastasis suppressor function in CMM. Our studies should provide novel and critical insights that can be pursued to combat melanoma in its advanced and lethal forms.

描述（由申请人提供）：皮肤恶性黑色素瘤（CMM）是最致命的皮肤癌，其发病率在美国和世界各地以惊人的速度增加。最近发现的晒黑床使用与年轻女性黑色素瘤发病率急剧增加之间的联系就证明了这一点。更好地了解 CMM 进展为转移形式的机制可能为提高生存率提供重要的新治疗方法。对转移抑制基因（如 NM23-H1（小鼠 NM23-M1））的研究为黑色素瘤转移的分子机制提供了新的见解。该应用基于我们的新观察结果，即 NM23-H1 是一种 3'-5' 核酸外切酶，可在体外对 DNA 发挥校对活性，其 3'-5' 核酸外切酶活性是转移抑制功能所必需的，并且该蛋白质促进修复UVR 诱导的 DNA 损伤。此外，为该项目开发的转基因小鼠模型首次重现了 NM23-H1 在 UVR 诱导的 CMM 中的转移抑制功能。我们的研究结果支持这样一种模型：NM23-H1 表达缺失会导致基因组完整性受损和突变，从而驱动 CMM 恶性进展。在具体目标 1 中，将在缺乏一种或两种异构体表达的转基因小鼠品系中确定 NM23-M1 和 NM23-M2 对紫外线辐射诱导的转移性黑色素瘤的贡献。在具体目标 2 中，将阐明 NM23 蛋白促进 DNA 修复途径的分子机制，并在细胞培养和肿瘤细胞解释模型系统中评估扰乱这些途径对转移抑制活性的影响。 Specific Aim 3 将针对原发性和转移性黑色素瘤应用全基因组测序和 RNA-seq 大规模并行测序的强大技术，以识别候选转移驱动的基因组改变和基因表达谱。拟议的研究将首次对特定 DNA 修复和转移抑制基因对抗恶性进展的相关途径进行系统分析，并首次将转基因小鼠模型应用于 CMM 转移抑制功能的研究。我们的研究应该提供新颖和批判性的见解，可以用来对抗晚期和致命形式的黑色素瘤。