MALAT1通过负调控 miR-31促进胆囊癌发生发展的分子机制研究

The prognosis of gallbladder carcinoma is really poor and its cause of death is mainly due to tumor recurrence and metastasis. Therefore, understanding the pathogenesis and mechanism of tumor recurrence and metastasis has great impact on the early diagnosis and better treatment outcome. Studies have reported that lncRNAs are involved in the carcinogenesis of many types of cancers including liver and breast cancers. However, the regulatory mechanism of lncRNA in the oncogenesis of gallbladder carcinoma was rarely known. MALAT1 is one of the lncRNAs which is associated with the regulatory pathways of various genes. Our preliminary studies indicated that MALAT1 is highly expressed in gallbladder carcinoma, and it exhibits important biological functions in the regulation of proliferation, apoptosis and metastasis in gallbladder carcinoma. At the same time, we also identified that miR-31 is involved in the occurrence and development of gallbladder cancer cell. Also, we have found that MALAT1 has a negative regulatory effect on miR-31. Based on our results, we propose to further explore the detailed molecular mechanism of how MALAT1 promotes the occurrence and development of gallbladder carcinoma. We will also study the mechanism of how MALAT1 interacts with and regulates miR-31 as well as its biological functions. Our study could help us pinpoint novel biomarker for the early diagnosis and indentify potential treatment target for gallbladder carcinoma.

胆囊癌预后极差，导致的死亡绝大部分是由于的肿瘤复发转移造成。因此，针对其发病和复发转移机制研究具有重要意义。有研究报道lncRNA与多种类型的肿瘤发生发展密切相关，但lncRNA对胆囊癌的调控机制报道较少。MALAT1是相关联基因数最多的lncRNA 之一，它在胆囊癌细胞中具有调控增殖、凋亡、转移的重要生物学功能。同时miR-31参与介导胆囊癌细胞的发生发展过程。我们前期工作确定了MALAT1 在胆囊癌中高表达，并且参与胆囊癌的发生，还鉴定了MALAT1 对miR-31具有负调控的作用。在此基础上，本课题将深入探究 MALAT1 促进胆囊癌发生发展的分子机制。研究其与miR-31相互作用机制与生物学功能，从而明确 MALAT1 作为胆囊癌诊治新靶点的临床意义。

胆囊癌是胆道系统恶性肿瘤的常见类型之一，具有很强的增殖、侵袭能力，预后极差。因此，针对其发生发展机制研究具有重要意义。基于前期研究成果，我们筛选了在胆囊癌组织中差异表达的lncRNA MALAT1作为研究对象，通过细胞学实验和动物模型，明确了MALAT1 胆囊中具有调控增殖、凋亡、转移等重要生物学功能。然后，我们进一步依据生物信息学分析和分子生物学实验，发现并验证了MALAT1/miR-31/E2F3之间的ceRNA网络调控机制，并探索了转录因子FoxA1对MALAT1的潜在调控机制，深入探讨了MALAT1作为胆囊癌诊治新靶点的临床意义。此外，我们还探究了在胆囊癌中高表达的另一条lncRNA DGCR5，发现DGCR5通过吸附miR-3619-5p并激活胆囊癌细胞中的MEK/ERK1/2和JNK/p38/MAPK途径发挥致癌作用。本课题在国家自然科学基金资助下对lncRNA在胆囊癌的作用展开了多项工作，共发表相关研究论文10篇，对我们系统认识lncRNA及其上下游调控机制在胆囊癌增殖、侵袭和转移中的作用具有重要指导性意义。