【摘 要】
：
间质细胞代谢重编程在调节肿瘤恶性进展过程中发挥重要作用。而结肠癌相关巨噬细胞(Tumor associatedmacrophage,TAM)的代谢活性尚未阐明。本研究将揭示结肠癌TAM来源的代谢因子及其在结肠癌恶性进展中的作用及机制。我们率先从细胞、动物实验及人体标本中证实：结肠癌可诱导TAM中ABHD5表达升高。我们成功构建了巨噬细胞特异的ABHD5转基因(TgABHD5)小鼠,并证实TAM中A
【机 构】
：
第三军医大学生物化学与分子生物学教研室,重庆,400038
【出 处】
：
中国生物化学与分子生物学会2016年全国学术会议
论文部分内容阅读
间质细胞代谢重编程在调节肿瘤恶性进展过程中发挥重要作用。而结肠癌相关巨噬细胞(Tumor associatedmacrophage,TAM)的代谢活性尚未阐明。本研究将揭示结肠癌TAM来源的代谢因子及其在结肠癌恶性进展中的作用及机制。我们率先从细胞、动物实验及人体标本中证实：结肠癌可诱导TAM中ABHD5表达升高。我们成功构建了巨噬细胞特异的ABHD5转基因(TgABHD5)小鼠,并证实TAM中ABHD5可促进结肠癌恶性进展：移植瘤及炎症诱发结肠癌增殖明显加快,荷瘤小鼠生存期显著缩短；同时在体外实验中,我们发现巨噬细胞ABHD5沉默(ABHD5-KD)可抑制结肠癌细胞增殖、周期进展及克隆形成。为探寻巨噬细胞ABHD5促进结肠癌增殖的机制,我们对巨噬细胞条件培养基(CM)进行了代谢组学分析。我们发现巨噬细胞CM中亚精胺可受ABHD5调控,并可抑制结肠癌细胞增殖。我们进一步构建了巨噬细胞特异的亚精胺合酶(SRM)转基因(TgSRM)小鼠模型,并证实了巨噬细胞ABHD5/SRM/亚精胺通路对结肠癌恶性进展的调控作用。为解析巨噬细胞ABHD5调控SRM转录的分子机制,我们构建了小鼠SRM基因启动子区域的连续截短报告基因,实验证明巨噬细胞中ABHD5对小鼠SRM的调控锁定在启动子区-750/-550区域。报告基因、突变实验及ChIP检测表明ABHD5可通过调节CEBPε转录调控SRM的表达。移植瘤实验也证实ABHD5/CEBPε可调节结肠癌恶性生长。那么,巨噬细胞ABHD5又是如何调控CEBPε活化的呢？我们进一步的实验表明,巨噬细胞ABHD5可抑制ROS产生,而清除ROS可阻断巨噬细胞ABHD5-KD诱导的SRM上调。移植瘤实验也表明,ROS清除可回复巨噬细胞ABHD5-KD对移植瘤的抑制作用。因此,我们认为ABHD5通过调节ROS产生,进而调控CEBPε依赖的SRM转录。综上,我们揭示了巨噬细胞ABHD5调控结肠癌恶性进展的全新功能及其潜在的分子机制,研究结果对于临床上预防和治疗结肠癌具有重要的理论指导意义。
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