曲酸诱导成纤维细胞产生的TGF-β在光动力学治疗黑色素瘤中的增敏机制

项目名称： 曲酸诱导成纤维细胞产生的TGF-β在光动力学治疗黑色素瘤中的增敏机制

项目编号： No.81672694

项目类型： 面上项目

立项/批准年度： 2017

项目学科： 医药、卫生

项目作者： 鲁元刚

作者单位： 中国人民解放军第三军医大学

项目金额： 25万元

中文摘要： 黑色素的过度表达是黑色素瘤（MM）抵抗光动力治疗（PDT）的关键因素，而曲酸可通过减少黑色素生成增加PDT治疗MM的敏感性。课题前期实验发现曲酸能诱导成纤维细胞产生TGF-β，通过抑制MITF调节黑色素生成，但具体机制不明。已知MITF受多种转录因子(如CREB 和GLI2)的调控，而我们的进一步研究发现，TGF-β可抑制转录因子CREB，但促进GLI2的表达。鉴此，本项目拟首先验证TGF-β是否通过调节转录因子CREB和GLI2抑制MITF，并探讨TGF-β 调节CREB和GLI2活性的可能作用位点；然后，利用MM三维侵袭模型和裸鼠荷瘤模型，观察曲酸能否通过诱导成纤维细胞分泌的TGF-β、抑制瘤细胞中MITF的表达、减少黑色素生成，最终增加PDT的治疗敏感性。本研究可为临床应用曲酸作为PDT治疗MM的增敏剂提供充足的实验依据，并可为晚期MM由于黑色素过多导致的放化疗抵抗提供新的治疗思路。

中文关键词： 黑色素细胞肿瘤；光动力学治疗；曲酸；黑素生成

英文摘要： Overexpression of melanin is a key factor for malignant melanoma resistance to photodynamic therapy(PDT). Kojic acid can increase melanoma cells susceptibility to PDT by reducing melanin production. Our preliminary experiments found that Kojic acid can induce TGF-β production in fibroblasts and regulate melanin synthesis by inhibiting MITF. But the exact mechanism is unknown.It is known that MITF is regulated by a variety of transcription factors such as CREB and GLI2. Our further study revealed that TGF-β could inhibit the transcription factor CREB while promote the expression of GLI2. In view of this, firstly, the project intends to verify that TGF-β can suppress MITF by regulating transcription factor CREB and GLI2, and to explore the possible site of action of CREB and GLI2 activation regulated by TGF-β. Then, based on three-dimensional MM invasion models and tumor-bearing nude mice model, the study will be carried out to elucidate whether kojic acid can induced secretion of TGF-β in fibroblasts, inhibit the expression of MITF, reducing melanin production, ultimately increasing the sensitivity of PDT for melanoma cells. These may provide sufficient experimental evidence for kojic acid to be a sensitizer in PDT for melanoma in clinic experience. In addition, it also provides a new treatment idea for metastatic melanoma resistance to chemotherapy and radiotherapy due to excessive melanin.

英文关键词： malignant melanoma;photodynamic therapy;kojic acid;melanogenesis