真皮成纤维细胞ATF3对黑色素瘤发生和发展的作用研究

Melanoma is the most devastating form of skin cancer, but it’s initiation is still not completely clear. Recent evidence suggested that the microenviromental change associated with senescent fibroblasts is an important driver of melanoma initiation and progression, but the underlying molecular mechanism needs to be clarified. ATF3 is a key stress response transcription factor, which negatively controls the expression of cytokines to block inflammation response. Our previous study showed that the upregulation of ATF3 in keratinocytes promotes the development of skin squamous cell carcinoma by blocking cellular senescence. The skin dermal fibroblast also expresses ATF3, but the role of ATF3 in skin dermal fibroblast hasn’t been studied. Our preliminary data showed significant lower expression level of ATF3 in dermal fibroblast derived from melanoma compared to normal fibroblast. To further study that the role of dermal fibroblast ATF3 in melanoma development, we will use our recent established grafting technology, a human skin model generated from cultured cells, to do in vivo study of human dermal fibroblast ATF3 function in the initiation and development of melanoma. In vitro mechanistic study, we will investigate the role of ATF3 controlling cellular senescence of dermal fibroblast and activation of cancer associated fibroblast. Finally, we will screen and validate compounds, which can control ATF3 expression in dermal fibroblast, and these compounds will have potential to develop a new target for the treatment of melanoma in the future.

黑色素瘤是恶性程度最高的皮肤肿瘤，最近研究表明：衰老的真皮成纤维细胞可促进黑色素瘤的发生，但其作用机制不很清楚。ATF3 是一重要应激反应性转录因子, 可直接抑制细胞因子的表达来拮抗炎症反应。研究显示：在皮肤表皮细胞中，ATF3可抑制细胞衰老从而促进表皮鳞状细胞癌的发生。皮肤真皮细胞同样表达ATF3，然而其功能却未见报道。本人前期工作中发现黑色素瘤标本中真皮成纤维细胞的ATF3表达水平明显低于正常细胞。为进一步探讨真皮细胞中ATF3对黑色素瘤的作用，本课题中将利用我们最近创建的移植细胞再生人皮肤技术，来体内研究真皮成纤维细胞中ATF3的表达对黑色素瘤发生和发展中的作用；研究ATF3如何调控真皮细胞衰老以及对肿瘤相关的成纤维细胞激活的作用，来阐明其促进黑色素瘤发生的作用机理；最后我们将筛选和验证调控真皮细胞中ATF3表达的化合物，为今后开发预防和治疗黑色素瘤提供新的靶向对象。

黑色素瘤的治疗仍然是一个困难的挑战。近来，将肿瘤基质为靶点以发展黑色素瘤治疗的策略已引起关注。激活转录因子3（ATF3）在调节肿瘤发生和发展中起着至关重要的作用，但是ATF3在人皮肤成纤维细胞（HDFs）中的表达是否会影响黑色素瘤的发生尚待研究。本项目的研究结果表明，人黑色素瘤基质细胞中的ATF3表达呈下调趋势。在体外，高水平表达ATF3的HDFs抑制黑素瘤细胞的增殖和迁移，并伴随着不同细胞因子（包括IL-6）的下调。在体内，具有高ATF3表达的HDFs降低了肿瘤的形成。向黑色素瘤细胞中添加人重组IL-6可以逆转那些体外和体内的作用，这表明HDFs的ATF3表达可通过IL-6 / STAT3途径调节黑色素瘤的进程。更重要的是，用环孢素A或苯乙双胍预处理HDFs以诱导ATF3表达可在体内外抑制黑素瘤细胞的生长。总而言之，我们的研究揭示了ATF3抑制人黑素瘤的生长，在HDFs中诱导ATF3的表达可以抑制黑素瘤的生长，这是一种潜在的黑素瘤治疗新方法。