茉莉酸甲酯通过SP1/c-Myc调控PKM2表达靶向抑制膀胱癌细胞能量代谢的研究

Bladder carcinoma is the most common urologic neoplasm in China. Energy metabolism of tumor cells has recently come into the focus of cancer research, and it has been stipulated that modulating cancer metabolism may provide therapeutic benefits. In a previous study, we found high expressions of glycolytic enzyme PKM2 in bladder cancer cells. On this basis, we plan to analyze the effect of PKM2 activity on energy metabolism in bladder cancer cells, and understand how this abnormal metabolism affects tumor cell growth.Recent studies have shown that new plant hormones “Methyl jasmonate” (MJ) downregulate the expression of the transcription factors c-Myc and SP1. c-Myc and SP1 regulate the transcription of PKM2 as well as the selective splicing of PKM2 pre-RNA.In this study, we will analyze how MJ alters energy metabolism in bladder carcinoma cells and elucidate its molecular mechanisms. Furthermore, we’ll aim to elucidate the mechanism of MJ’s selective cytotoxicity on cancer cells. This work will help us understand the effect of energy metabolism on the development of bladder cancer and provide a novel strategy for the treatment of bladder cancer. It will also guide us design and engineer MJ to obtain more selective and powerful agents for targeted therapy in bladder carcinoma.

膀胱癌是我国最常见的泌尿系统肿瘤,近年来肿瘤能量代谢"Warburg effect"成为研究热点,对肿瘤异常代谢通路的干预已被证明是潜在的靶向治疗途径。本课题组在前期实验发现膀胱移行细胞癌组织高表达糖酵解调节酶PKM2的基础上，拟通过研究膀胱癌细胞PKM2水平与肿瘤"Warburg effect"和生物学行为的联系，解析膀胱癌发生和进展中的特异性能量代谢途径以及关键调节蛋白；最近研究发现植物激素茉莉酸甲酯对转录因子SP1，c-Myc表达有调节作用，SP1和c-Myc分别是PKM2基因转录及其转录后pre-RNA剪切水平的关键调控因子，本课题组拟通过研究茉莉酸甲酯干预下,膀胱癌细胞PKM2水平和能量代谢改变及其作用机理,从而揭示茉莉酸甲酯肿瘤选择性细胞毒机制。本项目的顺利实施，将为膀胱癌治疗提供新的靶点与思路，并且为我们对茉莉酸甲酯进一步改造,获取高效高选择性药物起导向作用。

茉莉酸甲酯（Methyl Jasmonate, MJ）作为茉莉素家族活性最强的亚型，具有高选择、抗耐药的特性，其相关作用机制有待进一步阐明。通过本项目的开展，本课题组发现茉莉酸甲酯虽然可以对PKM2的表达水平进行调控，但此调控作用未能进一步对膀胱癌细胞乳酸代谢水平和葡萄糖消耗水平产生显著影响。另一方面，通过相关作用机制研究我们发现，茉莉酸甲酯能够能够显著提高膀胱癌细胞环状非编码RNA（circRNA）BCRC3的表达，而BCRC3能够作为“miRNA海绵”对miR-182-5p进行吸附，miR-182-5p可以与P27 mRNA 3’UTR相结合，在转录后水平下调P27表达。因此，茉莉酸甲酯可以通过促进BCRC3的表达，减少miR-182-5p对P27的抑制作用，促进P27的表达，从而在细胞和动物实验水平有效抑制膀胱癌的生长。本研究提高了茉莉酸甲酯的临床抗肿瘤认识，证实了BCRC3/miR-182-5p/P27通路对膀胱癌生物学活性的调控作用，进一步解析了膀胱癌发生发展机制，为下一步的靶向治疗思路提供理论基础。