外泌体microRNAs：肢端黑素瘤预后及干扰素治疗敏感性标志物筛选研究

项目名称： 外泌体microRNAs：肢端黑素瘤预后及干扰素治疗敏感性标志物筛选研究

项目编号： No.81502863

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： 石琼

作者单位： 中国人民解放军第四军医大学

项目金额： 18万元

中文摘要： 肢端黑素瘤是中国黑素瘤的高发类型，具有特殊的遗传背景、流行病学特征、发病机制及临床特点。干扰素是黑素瘤术后高危患者的主要辅助治疗药物，在针对肢端黑素瘤的治疗中发现，患者平均受益率低于欧美非肢端黑素瘤，亟待通过大样本临床研究筛选预后及干扰素治疗敏感性标志物以推进个体化治疗。我课题组发现肢端黑素瘤外泌体microRNAs表达谱具有疾病特异性，miR-25/93/106b异常高表达，生物信息学预测提示其可协同抑制STAT1/2，负向调控干扰素信号活化。本项目拟重点验证miR-25/93/106b表达水平与黑素瘤恶性进展的相关性，全面评估其作为肢端黑素瘤预后及干扰素治疗敏感性标志物的可行性，深入研究miR-25/93/106b通过细胞内外不同调控途径，分别靶向STAT1/2及MITF/ BCL2，负向调控干扰素信号活化及直接对抗干扰素促肿瘤凋亡作用的具体分子机制，为制定个体化治疗方案提供重要参考。

中文关键词： 黑素瘤；预后标志物；干扰素治疗；外泌体；微小RNA

英文摘要： Acral melanoma is the predominant melanoma subtype in Chinese, which has distinct clinical and epidemiological characteristics and a notably worse prognosis than common cutaneous melanoma. High-dose interferon (IFN) alfa-2b is the only adjuvant therapy for melanoma approved by the US Food and Drug Administration. Several studies have demonstrated that adjuvant therapy for high-risk melanoma patients with IFN alfa-2b improves disease-free survival (DFS), although the impact on overall survival (OS) is controversial. Besides, no association has been shown between outcome and dose or duration of treatment, suggesting that the few patients sensitive to interferon should be identified and sensitive markers for interferon treatment and prognosis are in great need. Recent studies have shown that exosome contain microRNAs (miRNAs), and cells can secrete miRNAs via exosomes and deliver them into recipient cells where the exogenous miRNAs can regulate target gene expression and recipient cell function. It is suggest that exosome microRNA can be used a marker in providing new means for individualized cancer treatments. Via microarray analysis, we identified 48 differentially expressed microRNAs of exosome in the plasma of acral melanoma patients. Among these microRNAs, miR-25-106b was selected for further study, as two of its predicted target genes, STAT1 and STAT2, play critical roles in type I IFN signaling. It has proved that PBMCs isolated from cancer patients exhibit depressed STAT1 phosphorylation in response to IFN-α, suggesting IFN signaling dysfunction. Thus, we well test and verify the potential role of miR-25-106b as sensitive markers for interferon treatment and prognosis of acral melanoma and demonstrate the exact regulatory mechanisms of exosome microRNA in abnormalities in innate immunity.

英文关键词： melanoma;prognostic biomarker;adjuvant interferon therapy ;exosome;microRNA