Suppression of Melanoma Initiation and Progression by NM23-H1

NM23-H1 抑制黑色素瘤的发生和进展

• 批准号: 8402060
• 负责人: David M Kaetzel
• 金额: $ 49.81万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 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/8402060
• 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; 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; RNA; 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; tumor growth

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. PUBLIC HEALTH RELEVANCE: While cutaneous malignant melanoma (CMM) is treated surgically with some success in its early stages, conventional treatments are ineffective once the disease has spread, or metastasized, to distant organs. This application is directed to elucidating the mechanisms that underlie metastasis in CMM, particularly that caused by overexposure to damaging ultraviolet radiation. These studies have considerable potential to improve diagnosis and prognosis of CMM patients, and to provide novel insights for effective treatments of the disease in its most advanced and lethal stages.

描述(申请人提供)：皮肤恶性黑色素瘤(CMM)是最致命的皮肤癌形式，其发病率在美国和世界各地以惊人的速度增长。暴露在破坏性紫外线辐射(UVR)下显然是这种疾病的危险因素，最近日光浴床的使用与年轻女性黑色素瘤发病率显著增加之间的联系证明了这一点。更好地了解CMM进展为转移形式的机制可能会为提高存活率提供重要的新的治疗方法。对转移抑制基因的研究，如NM23-H1(小鼠的NM23-M1)，为黑色素瘤转移的分子机制提供了新的见解。这一应用建立在我们新的观察结果的基础上，即NM23-H1是一个在体外对DNA发挥校对活性的3‘-5’外切酶，它的3‘-5’外切酶活性是肿瘤转移抑制功能所必需的，并且该蛋白促进了UVR诱导的DNA损伤的修复。此外，为该项目开发的转基因小鼠模型首次概括了NM23-H1在UVR诱导的CMM中的转移抑制功能。我们的发现支持一种模型，在该模型中，NM23-H1表达的丢失会导致基因组完整性受损和突变，从而推动CMM的恶性进展。在特定目标1中，NM23-M1和NM23-M2在紫外线辐射诱导的转移性黑色素瘤中的作用将在缺乏其中一种或两种亚型表达的转基因小鼠品系中确定。在特定的目标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干扰这些途径对转移抑制活性的影响。特指目标3将把大规模并行测序的强大技术应用于原发和转移性黑色素瘤的全基因组测序和RNA-SEQ，以确定驱动转移的候选基因组改变和基因表达谱。这些研究将首次系统分析特定的DNA修复和转移抑制基因对抗恶性进展的相关途径，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的和批判性的见解，可以用来对抗晚期和致命的黑色素瘤。 公共卫生相关性：虽然皮肤恶性黑色素瘤(CMM)在早期阶段的手术治疗取得了一定的成功，但一旦疾病扩散或转移到远处的器官，常规治疗就会无效。这项应用旨在阐明CMM转移的潜在机制，特别是过度暴露于破坏性紫外线辐射所引起的机制。这些研究有相当大的潜力来改善CMM患者的诊断和预后，并为疾病最晚期和致命阶段的有效治疗提供新的见解。