Department of Dermatology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China.
Int J Mol Med. 2020 Apr;45(4):1017-1026. doi: 10.3892/ijmm.2020.4478. Epub 2020 Jan 27.
Clinical studies have proven that ultraviolet B (UVB) based phototherapy can induce perifollicular and marginal repigmentation patterns in the skin of vitiligo patients. It is, however, difficult to conceive how melanocytes can easily exit from their tightly interconnected epidermal microenvironment to re‑enter a different location in the skin to establish a new network with neighboring keratinocytes. While it is known that matrix metalloprotease 9 (MMP9) is involved in the degradation of the extracellular matrix in physiological or pathological processes, little is known about whether MMP9 affects melanocyte migration in vitiligo repigmentation. To investigate the effects of the p53‑ transient receptor potential cation channel subfamily M member 1 (TRPM1)/microRNA (miR/miRNA)‑211‑MMP9 axis to regulate melanocyte migration following exposure to UVB, the expression profile of MMP9 in cultured human melanocytes transfected with or without the miR‑211‑mimic and p53‑GFP lentiviral vector, respectively were determined. Quantitative polymerase chain reaction and western blotting were used to examine p53, TRPM1 and MMP9 mRNA and protein levels in UVB‑exposed and unexposed cells. The capacity of melanocytes to migrate on collagen IV substrate was estimated using a Transwell migration assay. Interestingly, the upregulation of p53 and MMP9 at the mRNA and protein levels was evident in melanocytes treated with single or repeat exposures to UVB, whereas levels of TRPM1 and miR‑211 were significantly suppressed in UVB‑exposed melanocytes compared with the UVB‑unexposed control cells. These results indicate that the p53‑TRPM1/miR‑211‑MMP9 axis is significantly activated in melanocytes exposed to UVB. Notably, the ability of melanocyte migration was altered by the overexpression of p53 using a lentiviral vector and by the upregulation of miR‑211 using an miRNA mimic. That altered migration could be neutralized by co‑treatment with GM6001 (a broad‑spectrum MMP inhibitor). Overall, these results show that the MMP9‑mediated migration of melanocytes is regulated by a novel mechanism driven by the p53‑TRPM1/miR‑211‑MMP9 axis. Activation of the p53‑TRPM1/miR‑211‑MMP9 axis potentially represents an attractive therapeutic target to improve repigmentation outcomes in vitiligo patients.
临床研究已经证明，基于中波紫外线（UVB）的光疗可以诱导白癜风患者皮肤的毛囊周围和边缘复色模式。然而，很难想象黑素细胞如何轻易地从紧密相连的表皮微环境中脱离出来，重新进入皮肤的另一个位置，与邻近的角质形成细胞建立新的网络。虽然已知基质金属蛋白酶 9（MMP9）参与生理或病理过程中细胞外基质的降解，但目前还不清楚 MMP9 是否会影响白癜风复色中的黑素细胞迁移。为了研究 p53-瞬时受体电位阳离子通道亚家族 M 成员 1（TRPM1）/微小 RNA（miR/miRNA）-211-MMP9 轴在暴露于 UVB 后对黑素细胞迁移的调节作用，分别用 miR-211 模拟物和 p53-GFP 慢病毒载体转染培养的人黑素细胞，检测 MMP9 的表达谱。用定量聚合酶链反应和 Western blot 检测 UVB 暴露和未暴露细胞中 p53、TRPM1 和 MMP9 mRNA 和蛋白水平。用 Transwell 迁移实验评估黑素细胞在胶原 IV 底物上的迁移能力。有趣的是，在单次或重复暴露于 UVB 后，黑素细胞中 p53 和 MMP9 的 mRNA 和蛋白水平明显上调，而与未暴露于 UVB 的对照细胞相比，TRPM1 和 miR-211 的水平明显下调。这些结果表明，p53-TRPM1/miR-211-MMP9 轴在暴露于 UVB 的黑素细胞中被显著激活。值得注意的是，使用慢病毒载体过表达 p53 和使用 miRNA 模拟物上调 miR-211 可以改变黑素细胞的迁移能力。用 GM6001（一种广谱 MMP 抑制剂）共同处理可以中和这种改变的迁移能力。总的来说，这些结果表明，MMP9 介导的黑素细胞迁移受 p53-TRPM1/miR-211-MMP9 轴驱动的新机制调节。激活 p53-TRPM1/miR-211-MMP9 轴可能成为改善白癜风患者复色效果的有吸引力的治疗靶点。
