膀胱癌是泌尿道最常见的恶性肿瘤，阐明膀胱癌发生的分子机制进而寻求肿瘤标记物和治疗靶点具有重要意义。我们在前期研究中发现在膀胱癌标本中c-Met显著上调，而DLK1-DIO3印记域的50余个miRNAs却是显著下调，进一步的研究提示它们之间或能相互调控。因此，本研究拟从表观遗传学和转录因子调控两大途径探索c-Met对于DLK1-DIO3印记域miRNAs簇表达的影响，以及拟利用生物信息学和荧光素酶双报告系统等手段探索DLK1-DIO3印记域中可靶向调控c-Met的miRNAs筛选和验证，从而能够阐明c-Met和DLK1-DIO3印记域miRNAs簇相互调控的具体机制。此外，我们将探索利用新型CRISPR-on技术全面上调DLK1-DIO3印记域抑癌miRNAs簇的表达来抑制膀胱癌生长和转移的可能性。本项目的成功实施一方面将对膀胱癌的发生机制作一补充，另一方面将为肿瘤的靶向治疗提供新的策略。

Urinary bladder cancer is the most common urogenital malignant tumor. To elucidate the molecular mechanism of bladder cancer is important for seeking tumor markers and therapeutic targets. In our previous research, we found that c-Met was overexpressed in bladder cancer, whereas more than 50 miRNAs within the DLK1-DIO3 genomic region was down-regulated. In addition, there appears to exist a reciprocal regulation between them. Therefore, our current study intends to explore the epigenetic and transcriptional regulation role of c-Met in miRNAs within the DLK1-DIO3 genomic region. We would also try to identify the miRNAs within the DLK1-DIO3 genomic region that could directly regulate the expression of c-Met. Finally, we will adopt a novel endogenous gene activation technique, namely CRISPR-on system, to activate the expression of miRNAs within the DLK1-DIO3 genomic region and subsequently evaluate its effects on proliferation and metastasis of bladder cancer. Successful completion of these experiments is supposed to illustrate the functional role of c-Met and miRNAs in bladder tumorigenesis and provide novel strategies for the targeted therapy of bladder cancer.