The Regulatory Mechanism of Differentiation and Growth by Prostaglandin D2 in Pigment Cells

小眼症相关转录因子（Mitf）负责黑素细胞的分化。黑眼白色（Mi-bw）小鼠是一种隐性Mitf突变体，由于Mitf表达受损，毛囊和内耳中缺乏黑素细胞，从而表现出白色毛色和耳聋。通过对野生型和Mi-bw小鼠皮肤的cDNA微阵列分析，我们确定了脂质运载蛋白型前列腺素D合成酶（L-PGDS）作为一种新的黑素细胞标志物。L-PGDS通过产生前列腺素D_2（PGD_2）发挥多种生物学作用。有趣的是，通过北方印迹和RT-PCR分析判断，L-PGDS在正常人表皮黑素细胞中表达，但在人黑素瘤细胞系中不表达。这些意想不到的发现促使我们研究L-PGDS是否是一种潜在的肿瘤抑制剂。因此，我们使用HMV-Ⅱ、SK-MEL-28、624 mel和G361细胞系检测了PGD_2对人黑素瘤细胞生长的影响。PGD_2对黑色素瘤细胞的生长有明显的抑制作用，而对PGD_2受体特异性激动剂DP_1或DP_2则无明显抑制作用，提示PGD_2可能通过一种不依赖于已知PGD_2受体的机制抑制黑色素瘤细胞的生长。因此，L-PGDS在黑色素瘤细胞中表达的丧失可能有利于它们的生长。这些结果表明，L-PGDS可能作为一个潜在的肿瘤抑制剂在人黑色素瘤细胞。

Microphthalmia-associated transcription factor (Mitf) is responsible for differentiation of melanocytes. The black-eyed white (Mi-bw) mouse, a recessive Mitf mutant, lacks melanocytes in hair follicles and inner ear due to the impaired expression of Mitf, thereby exhibiting white coat color and deafness. By cDNA microarray analysis between wild type and Mi-bw mouse skin, we have identified lipocalin-type prostaglandin D synthase (L-PGDS) as a new melanocyte marker. L-PGDS exerts various biological actions in part via production of prostaglandin D_2 (PGD_2). Interestingly L-PGDS is expressed in normal human epidermal melanocytes, but not in human melanoma cell lines, as judged by northern blot and RT-PCR analyses. Such unexpected findings prompted us to examine whether L-PGDS is a potential tumor suppressor. Accordingly, we examined the effect of PGD_2 on the cell growth of human melanoma cells, using HMV-II, SK-MEL-28, 624mel, and G361 cell lines. The growth of melanoma cells was significantly repressed by the treatment with PGD_2, but not with each agonist specific for the PGD_2 receptor, DP1 or DP2, suggesting that PGD_2 may repress the growth of melanoma cells through a mechanism independent of the known PGD_2 receptor. Thus, the loss of L-PGDS expression in melanoma cells may be beneficial for their growth. These results suggest that L-PGDS may function as a potential tumor suppressor in human melanoma cells.