前列腺癌肝转移灶中酮体代谢通路变化的研究  

Changes of ketone body metabolism pathway in liver metastases of prostate cancer

作　　者：杜亘俣 朱鹤[1] 鲍伟 DU Genyu;ZHU He;BAO Wei(Department of Urology,Renji Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200127,China)

机构地区：[1]上海交通大学医学院附属仁济医院泌尿科,上海200127 [2]上海交通大学医学院附属仁济医院上海市肿瘤研究所

出　　处：《上海医学》2023年第10期668-675,共8页Shanghai Medical Journal

基　　金：2022年上海市“超级博士后”激励计划(2022406)。

摘　　要：目的探究前列腺癌肝转移灶中酮体代谢通路及其相关基因表达的变化。方法选取前列腺癌基因编辑小鼠模型Pbsn-Cre,RB 1^(floxp/floxp)P 53^(floxp/floxp)(RB 1^(Δ/Δ)P 53^(Δ/Δ))小鼠的原位灶(5个)和对应的肝转移灶(2个)组织样本,及原位灶(3个)和肝转移灶(2个)来源的类器官样本,进行RNA测序(RNA-Seq)分析。通过公共数据库cBioPortal获取前列腺癌患者原位灶(N=5)及肝转移灶(N=26)样本的测序数据。对小鼠和患者的相关测序数据进行基因表达差异分析,以及基因集富集分析(Gene Set Enrichment Analysis,GSEA)和京都基因和基因组百科全书(Kyoto Encyclopedia of Genes and Genomes,KEGG)的通路富集分析。将RB 1^(Δ/Δ)P 53^(Δ/Δ)小鼠肿瘤组织来源的类器官接种至11只实验组C57BL/6J小鼠的前列腺构建前列腺癌肝转移模型,收集实验组原位灶及肝转移灶肿瘤组织,各11个,以及实验组相对正常的肝组织与对照组小鼠正常肝组织,各6个,应用实时荧光定量PCR反应(qRT-PCR)检测酮体代谢通路相关基因的表达变化。结果在小鼠的数据中,与前列腺癌原位灶相比,肝转移灶的细胞酮体代谢通路、细胞酮体代谢调控通路和调控酮体代谢的过氧化物酶体增殖物激活受体(peroxisome proliferators-activated receptor,PPAR)信号通路均显著富集(P值均<0.01)。在患者数据中,与前列腺癌原位灶相比,上述3条通路在肝转移灶中也显著富集(P值均<0.01)。对小鼠的RNA-Seq数据中有显著变化的差异基因进一步行KEGG富集分析,结果显示PPAR信号通路在小鼠来源的组织样本中显著富集(P<0.05)。在小鼠的RNA-Seq数据中,与前列腺癌原位灶相比,肝转移灶中酮体代谢过程的相关基因HMGCS 2、SLC 27 A 5的log 2[差异倍数(FC)]表达量均显著上调(P值均<0.05)。与小鼠类器官的前列腺癌原位灶相比,肝转移灶中参与酮体转运的SLC 16 A 7的log 2(FC)表达量显著下调(P<0.05)。与患者的前列腺癌Objective To investigate the pathway and related genes of ketone body metabolism in liver metastases of prostate cancer.Methods The samples were obtained from Pbsn-Cre,RB1^(floxp/floxp)P53^(floxp/floxp)(RB1^(Δ/Δ)P53^(Δ/Δ))mouse,a gene-edited mouse model of prostate cancer.The orthotopic tumor(n=5)and the corresponding liver metastatic tumor(n=2)tissue samples of RB1^(Δ/Δ)P53^(Δ/Δ)mice,and the organoids derived from orthotopic tumor(n=3)and the corresponding liver metastatic tumor(n=2)were analyzed by RNA sequencing(RNA-Seq).Patient sequencing data of prostate orthotopic tumor(n=5)and liver metastatic tumors(n=26)were obtained from the public database cBioPortal.Gene expression difference analysis,gene set enrichment analysis(GSEA)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis were performed for the sequencing data of mice and patients.The organoids derived from RB1^(Δ/Δ)P53^(Δ/Δ)tumor tissue were inoculated into the prostate of 11 C57BL/6J mice of experimental group to construct a prostate cancer liver metastatic model.And the orthotopic tumor tissues(n=11),liver metastatic tumor tissues(n=11),relatively normal liver tissues(n=6)from experimental group and normal liver tissues(n=6)from control group were collected.Real-time quantitative PCR(qRT-PCR)was used to detect the changes in gene expression related to ketone body metabolism pathway.Results In RNA-Seq analysis,ketone metabolism-related pathways and peroxisome proliferators-activated receptor(PPAR)signaling pathways were significantly enriched in liver metastatic tumor tissues compared with orthotopic tumor tissues in the samples of mice and patients(P<0.01).KEGG enrichment analysis showed that PPAR pathways were significantly enriched in tissue samples from mice(P<0.05).In all mouse samples,the gene for 3-hydroxy-3-methylglutaryl-CoA synthase 2(HMGCS2),a key rate-regulating enzyme involved in ketone body production,and solute carrier family 27 member 5(SLC27A5)were significantly overexpressed in liver metastases compared wi

关 键 词：前列腺癌 酮体代谢 肝转移 羟甲基戊二酰辅酶A合酶2 溶质载体家族27成员5 

分 类 号：R737.25[医药卫生—肿瘤]