The Etiology of UV-Induced Melanoma

描述（由申请人提供）：与阳光诱导的鳞状细胞癌（SCC）相比，皮肤恶性黑色素瘤（CMM）的病因尚不清楚。特别是，阳光照射和DNA损伤在CMM发生中的作用是一个悬而未决的问题。Richard Setlow使用xiphohorus回交杂交模型进行的早期癌变研究表明，暴露于阳光的DVB成分引起的直接DNA损伤对于黑色素瘤的形成是必要和充分的。Setlow随后的研究表明，不被DNA直接吸收的单色UVA辐射也足以诱导xiphohorus的黑色素瘤。这些结果对公共健康有重大影响，表明尽管使用防晒霜可以抑制uvb引起的红斑，但实际上可能会增加暴露在导致黑色素瘤的UVA波长下。随后，全世界就防晒霜的使用和“滥用”展开了激烈的公开辩论，一直持续到今天。因此，许多外行人和科学家一直认为CMM主要是由与UVA相关的自由基机制引起的，而不是由DNA直接吸收UVB造成的损伤引起的。我们的数据不支持自由基化学在黑色素瘤诱导中的主要作用。相反，我们认为DNA吸收UVB波长引起的直接损伤（例如，环丁烷嘧啶二聚体或CPD）是形成CMM所必需的，修复这些损伤的能力在肿瘤易感性中起着重要作用。该项目的具体目标是通过检查(1)易患的剑鱼回交杂交鱼黑色素瘤形成的波长和DNA损伤依赖性，(2)剑鱼核苷酸切除修复的遗传多样性和遗传，以及(3)易患的黑色素瘤杂交模型中的基因表达及其在紫外线下的调节来验证这些想法。通过这些研究，我们希望确定黑色素瘤的有效太阳波长边界，确定对CMM至关重要的DNA损伤类别，并阐明DNA修复在肿瘤抑制中的作用。

DESCRIPTION (provided by applicant): In contrast to sunlight-induced squamous cell carcinoma (SCC) the etiology of cutaneous malignant melanoma (CMM) is not well understood. In particular, the role that sunlight exposure and DNA damage play in the initiation of CMM is an open question. Early carcinogenesis studies by Richard Setlow using the Xiphophorus backcross hybrid model indicated that direct DNA damage caused by exposure to the DVB component of sunlight is necessary and sufficient for melanoma formation. Subsequent studies by Setlow showed that monochromatic UVA radiation that is not directly absorbed by DNA was also sufficient for melanoma induction in Xiphophorus. These results had significant public health consequences, suggesting that although sunscreen use may inhibit UVB-induced erythema it may actually increase exposure to the UVA wavelengths that cause melanoma. An intensive worldwide public debate on sunscreen use and "abuse" ensued that is still engaged today. Consequently, there persists a perception among many laymen and scientists that CMM is primarily caused by free radical mechanisms associated with UVA rather than by damage resulting from direct absorption of UVB by DNA. Our data do not support a major role of free radical chemistry in melanoma induction. To the contrary, we believe that the direct damage caused by the absorption of UVB wavelengths by DNA (e.g., the cyclobutane pyrimidine dimer or CPD) is required for CMM formation and that the ability to repair these lesions plays a significant role in tumor susceptibility. The specific aims of this project are designed to test these ideas by examining (1) the wavelength- and DNA damage-dependence of melanoma formation in susceptible Xiphophorus backcross hybrid fish, (2) the genetic diversity and inheritance of nucleotide excision repair in Xiphophorus, and (3) gene expression and its modulation by UV in a melanoma susceptible hybrid model. From these studies we hope to define the effective solar wavelength boundaries of melanoma, identify the class of DNA damage critical to CMM and elucidate the role of DNA repair in tumor suppression.