肢端及粘膜型黑色素瘤相关的microRNA表观遗传调控研究

Acral and mucosal melanoma is extremely rare in Caucasian melanoma patients, but a higher incidence of yellow people. Epidemiological studies in China document acral and mucosal melanoma incidence is about 75%. The occurrence of acral and mucosal melanoma remain unclear. There is no effective treatment for patients with acral and mucosal melanoma and these patients show poor prognosis. Research progress in acral and mucosal melanoma is slow due to its low incidence in Caucasian. We intends to take full advantage of the clinical resources, to clarify the occurrence and systemic treatment approach of acral and mucosal melanoma. Preliminary work shows that the expression profile of microRNA in various types of melanoma were significantly different. Based on this finding, the following work will be done. Firstly, we want to investigate the expression patterns of microRNA in different types of melanoma by using small RNA sequencing. Furthermore, specific microRNA will be chosen to perform further confirmation and the effect of these microRNAs acting as therapeutic markers on acral and mucosal melanoma will be analyzed by cell lines and animal levels assay. Next, further epigenetic regulatory mechanism and function of these specific microRNA will be studied and a complex regulatory network motif will be probed. Finally, we also intend to clarify the difference of the effect of this regulatory network on the therapy of acral and mucosal melanoma. Taken together, This study aimed to explore a novel and systemic treatment approach for acral and mucosal melanoma.

肢端及粘膜型黑色素瘤在白种人黑色素瘤中极为少见，但在黄种人黑色素瘤中发病率较高，中国肢端及粘膜型黑色素瘤发病率约占65%。针对肢端及粘膜型黑色素瘤尚无有效治疗手段，患者预后极差。由于发病率低，西方国家有关肢端及粘膜型黑色素瘤研究进展缓慢。申请者前期工作显示，microRNA在不同类型黑色素瘤中的表达谱存在显著差异。以此为线索，申请者拟利用独特的临床资源开展以下研究：1）利用小RNA测序技术建立不同类型黑色素瘤的microRNA差异表达谱，选择肢端及粘膜型黑色素瘤特异表达的microRNA进行验证，并在细胞及动物水平探讨其作为评估疗效标志物的有效性；2）选择特异表达下调的microRNA进行深入的表观遗传调控机制及分子机制研究，以期建立microRNA介导的反馈调节网络；3）探讨上述调控网络在不同类型黑色素瘤发病机制及治疗应答等方面的功能差异，为建立肢端及粘膜型黑色素瘤有效治疗方案奠定基础。

粘膜型黑色素瘤在白种人黑色素瘤中极为少见，但在黄种人黑色素瘤中发病率较高，中国粘膜型黑色素瘤发病率约占25%。针对粘膜型黑色素瘤尚无有效治疗手段，患者预后极差。由于发病率低，西方国家有关粘膜型黑色素瘤研究进展缓慢，miRNA在该领域的研究鲜有报道。迄今仅有1篇2010年发表在Plos one的文章涉及粘膜型黑色素瘤相关的miRNA研究。申请者所在科室建立了中国黑色素瘤临床-病理-遗传分析数据库，目前该数据库拥有完整的中国黑色素瘤临床随访与生物学标本5000余例，其中粘膜型黑色素瘤队列超过1000例，在此基础上建立了粘膜黑色素瘤 miRNA 差异表达谱；明确了特定miRNA对粘膜黑色素瘤细胞株恶性表型的影响；确定了表达失调miRNA与粘膜黑色素瘤预后的相关性。建立了中国黑色素瘤患者PDGFRA、mTOR、GNAQ、GNA11等基因突变谱，为全国黑色素瘤患者的个体化治疗提供依据。. 在本项基金的资助下，获得如下成果：发表SCI收录论著6篇，累计影响因子38.669分。出版《黑色素瘤》专著一部，主持编写并推出2013和2015版《中国黑色素瘤诊治指南》。发表美国临床肿瘤学年会（ASCO）等国际大会报告3篇，全国临床肿瘤学年会（CSCO）等国内大会报告2篇。培养博士研究生6人，硕士研究生5人。