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

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.

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。

我国膀胱癌的发病率高居泌尿系恶性肿瘤第1位，目前极少有针对膀胱癌的靶向药物进入临床试验阶段或被批准用于膀胱癌的治疗。近年来多项研究发现自噬在肿瘤的发生、发展过程中发挥重要作用，但自噬在膀胱尿路上皮癌中的机制研究少有报道。课题研究期间，我们主要完成了以下工作：阐述了SMYD3在膀胱尿路上皮癌细胞自噬中的调控作用，明确了自噬与膀胱癌细胞生物学行为的关系；具体为：（1）SMYD3 在膀胱癌中的表达异常升高，抑制 SMYD3 表达可诱导膀胱癌细胞自噬；（2）SMYD3 介导的自 噬变化调控膀胱癌细胞的增殖和凋亡；（3）SMYD3 可能通过 mTOR 通路参与调控膀胱癌细胞的自噬、凋亡和增殖。本课题为膀胱癌的发病机制研究提供可靠线索和途径，为膀胱癌的靶向治疗提供创新性的思路。