组蛋白甲基化酶SMYD3在膀胱尿路上皮癌中的调控及作用机制研究

膀胱尿路上皮癌是泌尿外科常见恶性肿瘤之一，目前尚无经批准的适用于膀胱癌的靶向治疗方案。膀胱癌的发生与发展以一系列信号传导通路、遗传学及表观遗传学的异常变化为基础，近来发现染色质组蛋白甲基化等表观遗传学异常和PI3K/AKT/mTOR通路的异常激活在膀胱癌的发生发展中起到重要作用。.我们近期研究发现：1.组蛋白甲基化酶SMYD3在膀胱癌发生发展中起到关键作用；2.SMYD3通过组蛋白甲基化酶活性诱导IGF-1R表达，从而激活AKT/mTOR级联；3.SMYD3在膀胱癌中的异常表达与其启动子区低甲基化以及转录因子E2F-1的激活作用有关。本项目旨在探讨：1. SMYD3在膀胱尿路上皮癌中的作用及作用机制，特别是SMYD3对其靶基因及下游通路的激活机制； 2.SMYD3在膀胱癌中的表达调控机制。本研究所获结果将有助于阐明膀胱癌的发病机制，并为该疾病的早期诊断及靶向治疗提供新思路。

Urothelial carcinoma of bladder is a common urologic malignant disease. No target therapy against bladder cancer has been issued so far. The development and progression of bladder cancer is based on the deregulation of a series of signaling pathway and genetic/epigenetic characters. Recently, it was found that aberrant in histone methylation status and over-activation of PI3K/AKT/mTOR cascade played a pivotal role in the tumorigenesis and progression of bladder cancer. .Our current data indicate that (1) histone methyltransferase SMYD3 plays critical role in the development and progression of bladder cancer; (2) SMYD3 activates AKT/mTOR cascade through inducing IGF-1R expression, which is dependent on its methyltransferase activity; (3) over-expression of SMYD3 in bladder cancer is associated with hypo-methylaiton in its promoter region and the transcriptional activity of transcription factor E2F-1. Our project aims to (1) explore the underlying mechanism/s that SMYD3 promotes the tumorigenic phenotypes of bladder cancer, focusing on the target genes and downstream pathways of SMYD3; (2) to delineate the mechanism/s of SMYD3 expressional regulation. The project promises to provide further mechanistic understanding of the pathogenesis of bladder cancer and pave a novel approach toward early diagnosis and target therapies of the disease.