Ahmad N, Gilliam A C, Katiyar S K, O'Brien T G, Mukhtar H
Department of Dermatology, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, Ohio 44106, USA.
Am J Pathol. 2001 Sep;159(3):885-92. doi: 10.1016/S0002-9440(10)61764-6.
Excessive exposure of solar ultraviolet (UV) radiation, particularly its UVB component, to human skin is the major cause for more than a million new cases of cutaneous malignancies diagnosed annually in the United States. Photocarcinogenesis, like other cancers, is a multistep process that includes initiation and promotion. A proper understanding of the molecular events occurring during the tumor promotion phase of photocarcinogenesis could lead to the development of novel approaches for the management of skin cancer. Using a transgenic mouse model (K5/ODC mice), which overexpresses the enzyme ornithine decarboxylase (ODC) in hair follicle keratinocytes, we studied the role of this gene in photocarcinogenesis. A single UVB-exposure of 180 mJ/cm(2) to the transgenic mice resulted in a minimal increase in bifold skin thickness and ODC activity. However, in SKH-1 hairless mice, the most common and highly sensitive model for photocarcinogenesis, and in littermate nontransgenic mice, increases in skin thickness and ODC activity were substantial. In long-term experiments, mice were exposed to 180 mJ/cm(2) of UVB radiation three times a week for 2 weeks (tumor-initiating dose). At 30 weeks after this treatment, in two independent experiments, 40% of the K5/ODC transgenic mice exposed to UVB were found to develop epidermal tumors. The tumors were histologically verified as benign papillomas and squamous cell carcinomas. Interestingly, 100% of the transgenic mice also developed >20 pigmented cysts/mouse, which contained keratinocyte material with increased keratinocytic melanization. Under similar UVB-exposure protocol, the nontransgenic littermates or SKH-1 hairless mice did not develop tumors or pigmented cysts for up to 50 weeks. Oral consumption of alpha-difluoromethylornithine, an irreversible specific inhibitor of ODC, in the drinking water (1% w/v) to the transgenic mice resulted in complete prevention of UVB-mediated tumorigenesis and a substantial decrease in the formation of pigmented cysts (<10 per mouse). These data establish a definitive role of ODC in the promotion phase of photocarcinogenesis.
太阳紫外线（UV）辐射，尤其是其中的UVB成分过度照射人体皮肤，是美国每年诊断出的超过100万例皮肤恶性肿瘤新病例的主要原因。光致癌作用与其他癌症一样，是一个多步骤过程，包括启动和促进阶段。正确理解光致癌作用肿瘤促进阶段发生的分子事件，可能会导致开发出治疗皮肤癌的新方法。我们使用一种转基因小鼠模型（K5/ODC小鼠），该模型在毛囊角质形成细胞中过表达鸟氨酸脱羧酶（ODC），研究了该基因在光致癌作用中的作用。对转基因小鼠单次暴露180 mJ/cm²的UVB，导致皮肤厚度和ODC活性的双折增加最小。然而，在SKH-1无毛小鼠（光致癌作用最常见且高度敏感的模型）以及同窝非转基因小鼠中，皮肤厚度和ODC活性的增加相当显著。在长期实验中，小鼠每周三次暴露于180 mJ/cm²的UVB辐射，持续2周（肿瘤启动剂量）。在此治疗后30周，在两项独立实验中，发现40%暴露于UVB的K5/ODC转基因小鼠发生了表皮肿瘤。这些肿瘤经组织学证实为良性乳头状瘤和鳞状细胞癌。有趣的是，100%的转基因小鼠还出现了每只小鼠>20个色素性囊肿，其中含有角质形成细胞物质，角质形成细胞黑色素化增加。在类似的UVB暴露方案下，非转基因同窝小鼠或SKH-1无毛小鼠在长达50周的时间内未发生肿瘤或色素性囊肿。给转基因小鼠口服饮用水中1%（w/v）的α-二氟甲基鸟氨酸（一种ODC的不可逆特异性抑制剂），可完全预防UVB介导的肿瘤发生，并使色素性囊肿的形成大幅减少（每只小鼠<10个）。这些数据确定了ODC在光致癌作用促进阶段的明确作用。
