Jung Hyejung, Oh Eok-Soo
Department of Life Sciences, The Research Center for Cellular Homeostasis, Ewha Womans University, Seoul, Korea.
Pigment Cell Melanoma Res. 2016 Jul;29(4):434-43. doi: 10.1111/pcmr.12480. Epub 2016 May 20.
Although topical tacrolimus (FK506) is known to promote repigmentation by increasing the pigmentation and migration of melanocytes, the mechanism through which FK506 regulates cell migration remains unclear. Here, we report that FK506 treatment enhanced cell spreading on laminin-332 and increased migration in both melanocytes and melanoma cells. Interestingly, FK506 also increased the expression of syndecan-2, a transmembrane heparan sulfate proteoglycan through c-jun terminal kinase activation. Moreover, siRNA-mediated reduction of syndecan-2 expression decreased FK506-mediated cell spreading and migration in melanoma cells and decreased focal adhesion kinase phosphorylation in both melanocytes and melanoma cells. Consistent with these effects on syndecan-2 expression, FK506 enhanced the membrane and melanosome localizations of PKCβII, a regulator of tyrosinase activity. This suggests that FK506 may play a dual regulatory role by affecting both melanogenesis and migration in melanocyte-derived cells. Interestingly, however, FK506 failed to show any synergistic effect on the migration of UVB-treated melanocyte-derived cells. Taken together, these data indicate that FK506 regulates cell migration by enhancing syndecan-2 expression, further suggesting that syndecan-2 could be a potential target for the treatment of patients with vitiligo.
尽管外用他克莫司（FK506）已知可通过增加黑素细胞的色素沉着和迁移来促进色素再生，但其调节细胞迁移的机制仍不清楚。在此，我们报告FK506处理可增强细胞在层粘连蛋白-332上的铺展，并增加黑素细胞和黑色素瘤细胞的迁移。有趣的是，FK506还通过激活c-jun末端激酶增加了跨膜硫酸乙酰肝素蛋白聚糖syndecan-2的表达。此外，siRNA介导的syndecan-2表达降低减少了FK506介导的黑色素瘤细胞的细胞铺展和迁移，并降低了黑素细胞和黑色素瘤细胞中的粘着斑激酶磷酸化。与这些对syndecan-2表达的影响一致，FK506增强了酪氨酸酶活性调节剂PKCβII的膜和黑素小体定位。这表明FK506可能通过影响黑素细胞衍生细胞中的黑素生成和迁移发挥双重调节作用。然而，有趣的是，FK506对紫外线B处理的黑素细胞衍生细胞的迁移未显示任何协同作用。综上所述，这些数据表明FK506通过增强syndecan-2表达来调节细胞迁移，进一步表明syndecan-2可能是白癜风患者治疗的潜在靶点。
