乙酰辅酶A羧化酶调控肝癌细胞增殖的效应与机制  

Effect and mechanism of acetyl-CoA carboxylase 1 in regulating the proliferation of hepatocellular carcinoma cells

作　　者：简阿妮 白雪霞 杨南飞 沈萍萍[1] JIAN Ani;BAI Xuexia;YANG Nanfei;SHEN Pingping(School of Life Sciences,Nanjing University,Nanjing 210023,China)

机构地区：[1]南京大学生命科学学院,南京210023

出　　处：《中国药科大学学报》2024年第6期783-794,共12页Journal of China Pharmaceutical University

基　　金：国家自然科学基金项目(No.82304492,No.82300139)。

摘　　要：为了探究巨噬细胞如何促进肝癌细胞的脂滴囤积,并深入研究脂滴的关键代谢酶在肝癌细胞恶性生物学中的作用,利用肿瘤相关巨噬细胞(tumor-associated macrophages,TAMs)上清液诱导Hepa1-6脂滴(lipid droplets,LDs)生成,发现TAMs中的白细胞介素10(interleukin-10,IL-10)能够促进脂滴的积累。乙酰辅酶A羧化酶(acetyl-CoA carboxylase alpha,ACC1)是脂肪酸合成的关键酶之一,影响着肝癌的发生发展。本研究发现,ACC1在LDhigh Hepa1-6中高表达,之后通过ACC1的小分子抑制剂、siRNA干扰和CRISPR-cas9敲除等手段阻断ACC1的活性,发现Hepa1-6脂滴积累降低,同时减少了Hepa1-6增殖的恶性生物学行为,促进了Hepa1-6发生凋亡事件。综上所述,TAMs释放的IL-10促进了肝癌细胞的脂滴形成,导致肝癌细胞的恶性增殖与凋亡。ACC1在TAMs促进肝癌细胞脂滴积累过程中发挥关键作用,并且可能受TAMs释放的IL-10的调控,这些发现可为肝癌治疗提供新的靶点。In order to investigate how macrophages promote lipid droplet hoarding in hepatocellular carcinoma cells and to delve into the roles of key metabolic enzymes of lipid droplets in the malignant biology of hepatocellular carcinoma cells,the present study was conducted to induce the generation of Hepa1-6 lipid droplets(LDs)using supernatants from tumor-associated macrophages(TAMs),and found that interleukin-10(IL-10)in TAMs was found to promote the accumulation of lipid droplets.Acetyl-CoA carboxylase alpha(ACC1)is one of the key enzymes for fatty acid synthesis and influences the development of hepatocellular carcinoma.In this study,ACC1 was found to be highly expressed in LDhigh Hepa1-6,and subsequent blockade of ACC1 activity by means of a small molecule inhibitor of ACC1,siRNA interference,and CRISPR-cas9 knockdown was found to reduce the accumulation of Hepa1-6 lipid droplets,as well as to reduce the malignant biological behavior of Hepa1-6 proliferation,and to promote the occurrence of apoptotic events.In summary,IL-10 released by TAMs promoted lipid droplet formation in hepatocellular carcinoma cells,leading to malignant proliferation and apoptosis of hepatocellular carcinoma cells.ACC1 plays a key role in the promotion of lipid droplet accumulation in hepatocellular carcinoma cells by TAMs and may be regulated by IL-10 released by TAMs,and these findings may provide a new target for hepatocellular carcinoma treatment.

关 键 词：肝癌 肿瘤相关巨噬细胞 代谢重编程 脂滴 乙酰辅酶A羧化酶1 

分 类 号：R735.7[医药卫生—肿瘤]