EPS8调控Hedgehog信号通路在恶性黑色素瘤发生发展中作用及机制研究

恶性黑色素瘤是全世界恶性程度最高的肿瘤之一，易早期出现转移、进展快、病死率高，且其相关发病机制尚不清楚，临床治疗效果不佳，严重影响人类生命健康。因此，阐明恶性黑色素瘤发生发展的具体机制意义重大。EPS8是EGFR激酶活性底物之一，在多种肿瘤的发生发展中发挥关键作用。项目组前期研究发现，EPS8在恶性黑色素瘤组织中高表达，且EPS8可促进Ptch1自噬、激活Hedgehog信号通路、调控恶性黑色素瘤细胞增殖凋亡和侵袭迁移，而下调Ptch1表达或抑制Hedgehog信号通路激活可阻滞EPS8对恶性黑色素瘤细胞增殖凋亡和侵袭迁移的调控作用。在此基础上，本项目拟分别在细胞、动物及临床水平阐明EPS8通过促进Ptch1自噬降解激活Hedgehog信号通路，调控恶性黑色素瘤细胞增殖凋亡及侵袭迁移，进而影响恶性黑色素瘤发生发展的具体机制，为恶性黑色素瘤的临床治疗提供新靶点。

Malignant melanoma is one of the most common malignant tumors in the world, and its incidence and mortality are high, which seriously threatens human life and health. At present, the molecular mechanism related to the occurrence and development of malignant melanoma is still not clear, which affects its clinical therapeutic effect. Therefore, it is of great significance to explore the mechanism of occurrence, development, invasion and metastasis of malignant melanoma. EPS8 is one of the active substrates of EGFR kinase and plays a key role in the development of various tumors. Our previous studies found that EPS8 is overexpressed in human malignant melanoma tissue and can promote the degradation of Ptch1 autophagy and interfere with Hedgehog signaling pathway and regulate the proliferation and apoptosis of malignant melanoma cells, but the specific mechanism is unclear. On this basis, the project aims to clarify the specific mechanism that EPS8 influences the apoptosis of malignant melanoma cells via the degradation of Ptch1 autophagy and subsequent activation of Hedgehog signaling pathway, which will provide a theoretical basis for targeted therapy of malignant melanoma.