侵袭转移是黑色素瘤高致死率的重要原因。近年研究表明环状RNA与肿瘤侵袭转移密切相关，但其对黑色素瘤作用不详。环状RNA可由基因前体mRNA可变剪接产生，申请人前期研究证实紫外线照射引起皮肤细胞mdm2基因可变剪接，前期实验表明紫外线照射促进mdm2基因8-10号外显子形成环状RNA circMdm2，在黑色素瘤细胞中高表达，过表达该环状RNA可提高NAE2水平，增强蛋白Neddylation修饰。据此提出circMdm2可通过Neddylation通路促黑色素瘤侵袭转移。为验证上述假设，本项目拟采用mini基因系统、RNA原位杂交和荧光定量PCR研究circMdm2的生成机制及其与黑色素瘤侵袭转移的关系。在此基础上，应用细胞和动物肿瘤模型进一步探索其通过与FMRP结合调控Neddylation通路促肿瘤侵袭转移的作用机制，为黑色素瘤侵袭转移的分子机制阐释及其诊断和治疗提供重要参考和理论依据

Melanoma leads to high mortality due to its invasion and metastasis. Accumulating evidence in recent years indicates circRNAs are closely associated with invasion and metastasis of cancers, however, the function and underlying mechanism of circRNA in melanoma remains obscure. CircRNAs result from alternative splicing process of gene pre-mRNAs and we previously found that UV irradiation caused alternative splicing of mdm2 gene. Our preliminary experiment showed that circRNA circMdm2, consisted by exons 8-10 of mdm2 gene, was elevated after UV irradiation and highly expressed in melanoma cells. overexpression of circMdm2 in skin cells could increase the NAE2 level and enhance protein neddylation, promoting cell migration and invasion. Here, we hypothesis that circMdm2 activates neddylation signal pathway to promote invasion and metastasis of melanoma. Mini-gene system will be utilized to understand the underlying mechanism of circMdm2 cyclization. RNA in situ hybridization and quantitative PCR will be used to analyze the correlation between circRNA expression and tumorigenesis ＆ metastasis. The effects of this circRNA on promoting melanoma invasion and metastasis by binding to FMRP and subsequently regulating neddylation signaling pathway will be investigated in cell and animal tumor models. The establishment of this research will benefit to elucidate the molecular mechanism underlying invasion and metastasis in melanoma and provide us new avenues for the diagnosis and treatment of melanoma.