SLC1A5通过促进M2型巨噬细胞极化促进肝癌进展  

SLC1A5 overexpression accelerates progression of hepatocellular carcinoma by promoting M2 polarization of macrophages

作　　者：邹金华[1] 王惠[1] 张冬艳[1] ZOU Jinhua;WANG Hui;ZHANG Dongyan(Department of Radiation Oncology,Nanfang Hospital,Southern Medical University,Guangzhou 510515,China)

机构地区：[1]南方医科大学南方医院放疗科,广东广州510515

出　　处：《南方医科大学学报》2025年第2期269-284,共16页Journal of Southern Medical University

基　　金：国家自然科学基金(82272719);广东省自然科学基金(2023A1515012724,2024A1515013249);广州市科技计划项目,2024年度基础与应用基础研究专题(2024A04J5205)。

摘　　要：目的探讨SLC1A5高表达在泛癌种的临床意义及其促进肝癌进展的机制。方法利用癌症基因组图谱(TCGA)、国际肿瘤基因组协会(ICGC)等数据库探讨SLC1A5在泛癌种的表达水平及其与临床分期、淋巴结转移及生存预后的关系;利用EPIC、CIBERSORT、TIMER算法分析SLC1A5与免疫细胞浸润的关系,分析SLC1A5联合M2型巨噬细胞浸润水平与肿瘤预后的关系。利用慢病毒过表达系统构建过表达SLC1A5肝癌细胞株;利用小干扰RNA(siRNA)构建沉默SLC1A5(NC组、si-SLC1A5-1组、si-SLC1A5-2组)的肝癌细胞株;CCK-8增殖实验检测SLC1A5对肝癌细胞增殖的影响;利用过表达SLCA5稳转株(NC组,SLC1A5过表达组)构建肝癌皮下瘤模型,体内水平探讨SLC1A5对肝癌增殖的影响;利用共培养体系验证干扰和过表达SLC1A5肝癌细胞对巨噬细胞极化的影响。结果SLC1A5主要定位于细胞膜上,SLC1A5在大多数肿瘤中均显著高表达(P<0.05),其表达水平与临床分期及淋巴结转移呈正相关(P<0.05);SLC1A5高表达与多癌种不良预后相关(P<0.05)。在13个癌种中显示SLC1A5与免疫评分呈正相关,二者相关性在低级别胶质瘤(LGG)、肝癌(LIHC)及甲状腺癌(THCA)中最显著(P<0.05)。多癌种显示SLC1A5与巨噬细胞浸润水平呈正相关(P<0.05),该相关性在LGG及LIHC中最显著;而在包括肺鳞癌、胰腺癌、胃癌在内的5种肿瘤中,二者呈负相关(P<0.05)。生存分析发现SLC1A5高表达且M2型巨噬细胞高浸润水平的患者生存预后最差(P<0.05);SLC1A5与免疫抑制相关基因、细胞因子及细胞因子受体表达呈正相关,该相关性在LGG、LIHC中最显著(P<0.05)。不同肝癌细胞株均高表达SLC1A5,过表达SLC1A5促进肝癌细胞增殖,干扰SLC1A5则抑制肝癌细胞增殖;体内实验验证过表达SLC1A5促进肝癌增殖。SLC1A5与M2型巨噬细胞极化分子标志物表达呈正相关,过表达SLC1A5促进M2型巨噬细胞极化并抑制T细胞分泌IFN-γ。结论SLC1A5与多种肿�Objective To investigate the clinical significance of SLC1A5 overexpression in pan-cancer and its mechanism for promoting hepatocellular carcinoma(HCC)progression.Methods We analyzed the correlation of SLC1A5 expression with clinical stage,lymph node metastasis and prognosis in pan-cancer using TCGA and ICGC datasets and explored its association with immune cell infiltration using EPIC,CIBERSORT,and TIMER algorithms.In HCC cell lines,the effects of lentivirus-mediated SLC1A5 overexpression or RNA interference on cell proliferation were examined using CCK-8 assay,and the growth of HCC cell xenografts overexpressing SLC1A5 was observed in nude mice.The effects of SLC1A5 overexpression or silencing in HCC cells on macrophage polarization were evaluated in a cell co-culture system.Results SLC1A5 was mainly localized on cell membrane and was highly expressed in most cancers in association with clinical stage,lymph node metastasis and poor prognosis.SLC1A5 expression was positively correlated with immunity score in 13 cancer types,especially in low-grade glioma(LGG),LIHC and thyroid cancer.SLC1A5 was positively correlated with macrophage infiltration level in LGG and LIHC but negatively correlated with macrophage infiltration in 5 cancers including lung squamous carcinoma,pancreatic carcinoma,and gastric carcinoma.Patients with SLC1A5 overexpression and high level of M2 macrophage infiltration had the worst survival outcomes.SLC1A5 was correlated with immunosuppression-related genes,cytokines,and cytokine receptors,which was the most obvious in LGG and LIHC.SLC1A5 was highly expressed in different HCC cell lines,and its overexpression promoted HCC cell proliferation both in vitro and in nude mice.In the cell co-culture experiment,SLC1A5 was positively correlated with the molecular markers of M2 polarization of macrophages,and its overexpression strongly promoted M2 polarization of the macrophages and inhibited T cell secretion of IFN-γ.Conclusion SLC1A5 expression level is correlated with clinical stage,lymph node met

关 键 词：泛癌 SLC1A5 M2型巨噬细胞 肝癌 增殖 

分 类 号：R73[医药卫生—肿瘤]