Tumor Suppressors in Spontaneous and UV-Induced Melanoma Models

遗传可能是皮肤恶性黑色素瘤(CMM)发展的一个强烈的诱因，CMM是一种发病率不断上升的致命癌症。尽管紫外线辐射被普遍认为在CMM中发挥了作用，但过度阳光暴露在黑色素瘤病因学中的作用仍存在争议。据预测，臭氧消耗会增加入射到地球表面的UVB辐射，可能会增加人类患CMM的风险。然而，UVA的比例代表了比增加人类黑色素瘤发病率更大的阳光成分，关键是开发和测试假设，将过度阳光暴露与黑色素瘤易感性的遗传因素联系起来，可以识别并潜在地隔离是必要的。在这个项目中，不同剑尾鱼物种杂交产生的遗传多样性将被用来开发和分析几个新的实验性黑色素瘤模型，目的是识别自发和艾滋病毒诱导的肿瘤发生的遗传决定因素。剑尾鱼黑色素瘤模型中紫外线诱导黑色素瘤形成的研究将为剑尾鱼黑色素瘤的发生以及剑尾蛇组织和细胞系中紫外线诱导的DNA损伤和修复建立紫外线作用谱。在这些模型中检测癌基因(Xmrk)和肿瘤抑制基因(CDKN2X，P53)在黑色素瘤中的作用的实验将解决关于Xmrk过度表达是否是剑尾蛇黑色素瘤的共同特征的假说。几个假说解决了抑制基因在这些肿瘤模型中的作用，包括抑制基因功能障碍是否由甲基化模式、启动子差异或结构变化决定。这些研究将有助于理解显性癌基因和肿瘤抑制基因如何在独特的剑鱼模型中促进肿瘤发生，但也将直接与理解人类黑色素瘤的形成有关，因为有证据表明CDKN2是人类黑色素瘤的易感基因。在这些独特的模式生物中研究CDKN2X、P53和DNA损伤将促进我们对黑色素瘤分子病因学的理解。

Heredity can be a strong predisposing factor in the development of cutaneous malignant melanoma (CMM), a deadly cancer which is increasing in incidence. Although UV radiation is generally believed to play a role in CMM, the role of excessive sunlight exposure in the etiology of melanoma is controversial. Ozone depletion, predicted to increase UVB radiation incident to the earth's surface, may increase the risk of CMM in the human population. However, UVA ration represents a much greater component of sunlight than increasing melanoma incidence in humans, it is crucial to develop and test hypotheses that correlate excessive sunlight exposure with genetic factors underlying melanoma susceptibility can be recognized and potentially isolated are necessary. In this project, the genetic diversity generated by the hybridization of different Xiphophorus species will be exploited to develop and analyze several new experimental melanoma models, with the goal of identifying genetic determinants of spontaneous and HIV-induced tumorigenesis. The investigation of UV-induced melanoma formation in Xiphophorus melanoma models will establish UV action spectra for melanomagenesis, and for UV-induced DNA damage and repair in Xiphophorus tissues and cell lines. Experiments to examine the roles of oncogenes (Xmrk) and tumor suppressor genes (CDKN2X, p53) in melanoma in these models will address hypothesis regarding whether Xmrk over-expression is a common feature of Xiphophorus melanomas. Several hypotheses address the roles of suppressor genes in these tumor models will be developed, including whether suppressor gene dysfunction is determined by methylation patterns, promoter differences, or structural alterations. These studies will contribute to an understanding of how dominant oncogenes and tumor suppressor genes contribute to tumorigenesis in the unique Xiphophorus models, but are also directly relevant to understanding melanoma formation in humans, because of the evidence implicating CDKN2 as a human melanoma susceptibility gene. Investigation of CDKN2X, p53, and DNA damage in these unique model organisms will advance our understanding of the molecular etiology of melanoma.