MAGE-A1在皮肤黑素瘤恶变过程中的功能和机制研究

Malignant Melanoma causes the most death of skin cancer, and the morbidity of melanoma is increasing every year. The epithelial-mesench ymal transition (EMT) and cancer stem cells (CSCs) are the key factors during the progression of tumor, such as metastasis, invasion, and so on. CSCs have the characteristic of EMT, and EMT can also drive part of tumor cells to get property of CSCs. In early days, we analysed transcriptome of melanoma cell lines, and get MAGE-A1 which was most associatied with melanoma progression. This factor was seldom reported in functions and regulations of melanoma. Our studies revealed that MAGE-A1 can promote melanoma cell metastasis and invasion, which were the features of EMT. This factor can also increases tumor proliferation, regulates phosphorylation of c-jun. Through comparing database of protein-protein interaction and research articles, we supposed that MAGE-A1 may constructs membrane complex with integrins and IGF1R, regulates ERK/MAPK and PI3K/AKT signaling, and then controls melanoma progression. In this project, we will use cell assays, mouse models, Co-IP, single cell sequencing to study the biological functions of MAGE-A1, and the molecular mechanism of which regulates CSCs, EMT, and signaling associated with cancer by MAGE-A1. The results will help use to understand the molecular mechanism of tumor process more effectively, and discover a potential biomark and target of tumor clinical diagnosis and therapy.

恶性黑素瘤在皮肤肿瘤中死亡率最高，发病率逐年增加。上皮-间充质转化(EMT)和肿瘤干细胞是造成肿瘤侵袭转移等恶性事件的关键因素。肿瘤干细胞具有EMT特征，EMT也可以使部分肿瘤细胞获得干细胞属性。我们前期转录组分析，筛选到与黑素瘤恶化关联密切的MAGE-A1表达异常，但其在黑素瘤中的功能和调控作用鲜有报道。研究显示，该因子可促进黑素细胞转移侵袭，具有一定的EMT特征。可促进增殖、调节c-jun磷酸化状态。通过筛选蛋白质相互作用数据库和文献检索，推测该因子可能与整合素和IGF1R等形成膜复合体，调节ERK/MAPK和PI3K/AKT信号通路，造成黑素瘤的恶变。本研究将利用细胞学，小鼠模型，免疫共沉淀，单细胞测序等技术探讨MAGE-A1的生物学功能和对黑素瘤干细胞、EMT的影响及信号通路的调控。研究结果将有助于了解恶性黑素瘤发生与恶化的分子机制，挖掘诊断和治疗的潜在生物标志物和治疗靶点。

黑素瘤是一种恶性程度高，转移率高，发病率高，预后差的疾病，发生转移的患者五年生存率不足10%。传统治疗手段对提高黑素瘤患者生存率效果极为有限。但随着生物制剂与靶向药，如PD-1，VEGF的出现，使患者生存率提高到30%左右，联合用药效果更为明显。因此，寻找新的致病原因，进一步发现新的治疗靶点对黑素瘤的治疗具有重大意义。课题组利用分子生物学从体外证实了MAGEA1使参与了黑素瘤恶变过程的重要分子，并从转录水平与蛋白水平验证了其调控通路与机制。我们的研究为黑素瘤的靶向治疗提供了新的治疗靶点与理论支持，在生物制药与分子技术领域具有重要的治疗意义与应用前景。