Okamoto Ichiro, Krögler Julia, Endler Georg, Kaufmann Stefan, Mustafa Stefan, Exner Markus, Mannhalter Christine, Wagner Oswald, Pehamberger Hubert
Department of Dermatology, Division of General Dermatology, Medical University of Vienna, Vienna, Austria.
Int J Cancer. 2006 Sep 15;119(6):1312-5. doi: 10.1002/ijc.21937.
Heme oxygenase-1 (HO-1) has been demonstrated to play an important role in the regulation of signaling systems, which are involved in the control of cell cycle progression and apoptosis. Recently, a (GT)n dinucleotide repeat polymorphism in the HO-1 promoter was shown to modulate HO-1 gene expression. Short (<25 GT) repeats are associated with an increased HO-1 upregulation after stimulation than are longer repeats. Malignant melanoma (MM) is the most serious cutaneous malignancy with high tendency to aggressive growth and resistance to apoptosis. Therefore, we sought to study the influence of this polymorphism on the progression of MM. We determined the HO-1 promoter genotype in 152 patients with MM and 398 healthy controls and studied their association in regard to susceptibility to MM, Breslow thickness and disease-free survival. In our study, the homozygous short allele with <25 (GT)n repeats (S/S) was found more frequently in the melanoma group compared to the healthy control population (21 and 12%, respectively). The calculated risk for acquiring primary MM in S/S carriers was 2-fold higher compared to those with L-allele types (95% confidence interval: 1.2-2.4, p = 0.03). Additionally, the S/S genotype was significantly associated with primary tumors with deeper Breslow thickness compared to L-allele (>25 repeats) carriers (mean Breslow thickness: 4.0 +/- 2.9 mm versus 3.1 +/- 1.7 mm, p = 0.03). These data suggest that HO-1 might render a higher risk for MM in S/S genotype individuals and could represent an important candidate gene in the pathogenesis and growth of malignant melanoma.
血红素加氧酶-1（HO-1）已被证明在信号系统调节中发挥重要作用，这些信号系统参与细胞周期进程和细胞凋亡的控制。最近，HO-1启动子中的（GT）n二核苷酸重复多态性被证明可调节HO-1基因表达。与较长重复序列相比，短（<25 GT）重复序列在刺激后与HO-1上调增加相关。恶性黑色素瘤（MM）是最严重的皮肤恶性肿瘤，具有侵袭性生长和抗凋亡的高倾向。因此，我们试图研究这种多态性对MM进展的影响。我们确定了152例MM患者和398例健康对照者的HO-1启动子基因型，并研究了它们在MM易感性、Breslow厚度和无病生存期方面的关联。在我们的研究中，与健康对照人群相比，黑色素瘤组中发现纯合短等位基因<25（GT）n重复序列（S/S）的频率更高（分别为21%和12%）。与携带L等位基因类型的人相比，S/S携带者患原发性MM的计算风险高出2倍（95%置信区间：1.2-2.4，p = 0.03）。此外，与L等位基因（>25重复序列）携带者相比，S/S基因型与Breslow厚度更深的原发性肿瘤显著相关（平均Breslow厚度：4.0 +/- 2.9 mm对3.1 +/- 1.7 mm，p = 0.03）。这些数据表明，HO-1可能使S/S基因型个体患MM的风险更高，并且可能是恶性黑色素瘤发病机制和生长中的一个重要候选基因。
