Skp2/Myc正反馈环路促进BRAF-V600E诱导黑素瘤EMT过程的机制和功能研究

项目名称： Skp2/Myc正反馈环路促进BRAF-V600E诱导黑素瘤EMT过程的机制和功能研究

项目编号： No.81502370

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 曲璇

作者单位： 陕西中医药大学

项目金额： 18万元

中文摘要： BRAF-V600E突变在恶性黑素瘤中最为常见，通过促进细胞侵袭和转移影响患者的生存预后。寻求调控该过程的关键分子对黑素瘤的诊断治疗具有重要意义。在前期研究中，我们发现癌基因Skp2在黑素瘤组织中呈高表达，受Myc转录激活调控，并参与诱导黑素瘤细胞EMT的发生。特别是，我们最近发现Skp2还是BRAF通路下游分子，并促进Myc对Snail的转录激活过程。因此，Skp2可能通过与Myc建立正反馈调控环路的方式诱导Snail的表达，并介导BRAF-V600E诱导细胞EMT的过程。本项目拟从临床样本入手分析BRAF突变、Skp2表达与黑素瘤分期预后的相关性；从分子水平阐明BRAF通路对Skp2的调控方式和诱导细胞EMT的机制；从细胞和动物水平探讨BRAF-V600E调控Skp2对黑素瘤侵袭、转移等生物学行为的影响。本研究对于黑素瘤的诊断治疗和预后评估、扩展Skp2临床应用价值均具有重要意义。

中文关键词： 黑色素细胞肿瘤；上皮-间质细胞转变；信号转导；转录调控；靶向治疗

英文摘要： BRAF-600E is the most commonly mutated gene in malignant melanoma, and has a serious impact on the survival and prognosis of clinical patients in the regulation of tumor invasion and metastasis. In order to fully address the related mechanism, our group analyzed the key factors involved in this process. We previously found that oncogene Skp2, which was highly expressed in melanoma tissues, was directly transactivated by Myc and induced Epithelial-Mesenchymal Transition (EMT) in melanoma cells. Remarkably, our recent study show that BRAF-V600E can induce Skp2 transcription through the regulation of Myc activity, and Skp2 can further activate Snail transcription via the interaction with Myc. Thus, we hypothesize that Skp2 induces Snail expression through the positive feedback loop with Myc, and mediates the induction of EMT by BRAF-V600E. In the current project, we are planning to start with analyzing the association of BRAF mutation and Skp2 expression with the tumor stage and prognosis in the clinical samples. Second, we are going to uncover the specific mechanism of Skp2 in the regulation of BRAF-V600E induced EMT in malignant melanoma. Finally, we will explore the impact of this regulation on cell malignancy, which contribute to the biological behavior alterations of malignant melanoma in both proliferation and metastasis. This project is critical for the significance of both the early diagnosis and treatment of malignant melanoma and extending the value of Skp2 in clinical application.

英文关键词： Melanoma;Epithelial-Mesenchymal Transition;Signal-transduction;Transcriptional regulation;Targeted Therapy