miR-9调控黑素细胞迁移参与白癜风发病及皮损复色的机制研究

Epidermal melanocytes anchoring to basal membrane and neighboring keratinocytes through various adhesion molecules to maintenance their normal quantity and function. Here, we speculate that the adhesion ability of melanocyte to surrounding structure decreased by internal and external environmental factors prompts melanocytes to migrate and finally lose from epidermis, comprising the critical step in vitiligo pathogenesis; as well as the reduced adhesion ability of perilesional melanocytes induce the migration of melanocytes to lesion epidermis, resulting in repigmentation of the white macules. MicroRNA-9(miR-9) is upregulated in vitiligo lesion, and mediated by UVB and tacrolimus, which targets the genes of some adhesion molecules especially E-cadherin mentioned above. By comparing the expression of miR-9 and its target adhesion molecules between the biopsy of vitiligo and normal skin in vivo, and observing the effects of miR-9 on melanocytic adhesion ability in the repigmentation induced by UVB or tacrolimus in a cellular model in vitro, this research prospectively clarify the mechanism of miR-9 regulated melanocyte migration on vitiligo onset and repigmentation.

表皮基底层黑素细胞通过各种黏附分子锚定于基底膜和邻近角质形成细胞，以维持其正常数量和功能。我们推测在各种内外因素作用下，黑素细胞与周围结构的黏附能力下降使其从表皮迁移脱失是白癜风发病的关键环节，而皮损周围正常黑素细胞黏附能力下降被诱导向皮损区迁移则导致白斑复色。miR-9在白癜风皮损区高表达，它的靶基因涉及以E-cadherin为代表的多种细胞黏附分子，且其表达受UVB和他克莫司调节。本研究通过比较不同时期白癜风皮损与正常皮肤中miR-9及其靶基因蛋白的表达，并构建体外细胞模型观察UVB或他克莫司治疗诱导白癜风复色过程中miR-9表达及其对黑素细胞黏附能力的影响，以阐明miR-9调控的黑素细胞迁移在白癜风发病和复色中的作用及可能机制。

白癜风是最常见的后天获得性色素脱失性疾病，累及全世界0.5~2%的人口，但发病机制不明。大量的组织学和免疫组化研究发现白癜风皮损区黑素细胞缺失，仅偶可见残存的无功能黑素细胞。基于此，近年来有学者提出用黑素细胞流失来解释白癜风发病。表皮黑素细胞具有严格的极性，通过多种黏附分子与基底膜和周边角质形成细胞结合，维持表皮正常功能。各种内外因素影响下，黑素细胞摆脱细胞间黏附从表皮中过度迁移脱失，被认为是白癜风发病的核心环节。与白癜风发病类似，复色过程中黑素细胞自毛囊或周边正常皮肤迁移也需摆脱其细胞间黏附。.本课题研究结果显示：①人白癜风皮损中miR-9表达增加，而黏附分子（如E钙黏素和β1整合素）表达下降；②中波紫外线（UVB）处理可上调角质形成细胞系（HaCaT）中IL-10表达，后者通过诱导miR-9甲基化而降低miR-9水平；③miR-9靶向并抑制HaCaT细胞中的E钙黏素和β1整合素；④miR-9抑制黑素细胞系（PIG1）向UVB处理的HaCaT细胞迁移。以上结果表明，在白癜风发病过程中，miR-9可能靶向抑制黏附分子表达而诱导黑素细胞丢失，而UVB照射可通过增加IL-10水平而下调miR-9水平，从而诱导黑素细胞复色损，这为理解白癜风发病机制和寻找新的治疗靶点提供了理论依据。