Mitchell David, Paniker Lakshmi, Sanchez Guillermo, Trono David, Nairn Rodney
Department of Carcinogenesis, The University of Texas MD Anderson Cancer Center, Science Park/Research Division, Smithville, Texas 78602, USA.
Mol Carcinog. 2007 Aug;46(8):679-84. doi: 10.1002/mc.20341.
In contrast to sunlight-induced squamous cell carcinoma 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 this deadly form of cancer is an open question. Early UV carcinogenesis studies in the Xiphophorus backcross hybrid fish model by Richard Setlow indicated that direct DNA damage caused by exposure to the UVB component of sunlight is necessary and sufficient for melanoma formation. Subsequent studies by Setlow suggested that monochromatic UVA radiation that is not directly absorbed by DNA was also sufficient for melanoma induction in Xiphophorus and was, indeed, primarily responsible for initiating human melanoma. These results had significant public health consequences, suggesting that although sunscreens may inhibit UVB-induced erythema they may actually increase exposure to the UVA wavelengths that cause cancer. An intensive worldwide public debate on sunscreen use and "abuse" ensued. Our data do not support a major role of free radical chemistry in melanoma induction. We find evidence 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. Using the Xiphophorus backcross hybrid fish we are currently in the process of re-evaluating the wavelength- and DNA damage-dependence of UV-induced melanoma and the role nucleotide excision repair and the genes controlling DNA repair and the UV response play in melanoma resistance. From these studies we hope to define the effective solar wavelength boundaries of melanoma, identify the class of critical DNA damage and elucidate the role of DNA repair in tumor suppression.
与阳光诱导的鳞状细胞癌不同，皮肤恶性黑色素瘤（CMM）的病因尚未完全明确。特别是，阳光照射和DNA损伤在这种致命癌症的引发过程中所起的作用仍是一个悬而未决的问题。理查德·塞特洛在剑尾鱼回交杂种鱼模型上进行的早期紫外线致癌研究表明，暴露于阳光中的UVB成分所导致的直接DNA损伤对于黑色素瘤的形成是必要且充分的。塞特洛随后的研究表明，未被DNA直接吸收的单色UVA辐射对于剑尾鱼黑色素瘤的诱导也是足够的，并且实际上是引发人类黑色素瘤的主要原因。这些结果产生了重大的公共卫生影响，表明尽管防晒霜可能会抑制UVB诱导的红斑，但它们实际上可能会增加对致癌UVA波长的暴露。一场关于防晒霜使用和“滥用”的激烈全球公众辩论随之而来。我们的数据不支持自由基化学在黑色素瘤诱导中起主要作用。我们发现有证据表明，DNA吸收UVB波长所造成的直接损伤（例如，环丁烷嘧啶二聚体或CPD）是CMM形成所必需的，并且修复这些损伤的能力在肿瘤易感性中起着重要作用。利用剑尾鱼回交杂种鱼，我们目前正在重新评估紫外线诱导黑色素瘤的波长和DNA损伤依赖性，以及核苷酸切除修复和控制DNA修复及紫外线反应的基因在黑色素瘤抗性中所起的作用。通过这些研究，我们希望确定黑色素瘤的有效太阳波长界限，识别关键的DNA损伤类别，并阐明DNA修复在肿瘤抑制中的作用。
