■过氧化物酶体增殖物激活受体(PPAR)在胃腺癌(STAD)的发生和发展中发挥多种功能。本研究分析了PPARs与免疫状态的关系,分子突变,和STAD的药物治疗。
■三个PPAR基因的表达谱(PPARA,PPARD和PPARG)从癌症基因组图谱(TCGA)数据集中下载,以分析其在泛癌症中的表达模式。PPARs与临床病理特征之间的关联,预后,肿瘤微环境,还探索了基因组突变和药物敏感性。使用Pearson分析计算两个PPAR基因之间的共表达。使用基因集变异分析(GSVA)软件包对PPAR的调节途径进行评分。定量实时聚合酶链反应(qRT-PCR),蛋白质印迹,进行细胞计数试剂盒-8(CCK-8)测定和transwell测定以分析PPAR基因在STAD细胞系(AGS和SGC7901细胞)中的表达和功能。
■PPARA,当与TCGA中的大多数32型癌症相比时,PPARD和PPARG在STAD样品和细胞系中更异常表达。在STAD中,PPARD在3+4级和男性患者中表达较高,而PPARG在3+4级和年龄>60岁的患者中更高。高PPARA表达组的患者往往具有更长的生存时间。共表达分析显示6个基因与STAD中的3个PPAR基因显著相关。单样本GSEA(ssGSEA)显示三个PPAR基因在23条通路中富集,包括MITOTIC_SPINDLE,MYC_TARGETS_V1、E2F_TARGETS与免疫细胞密切相关,包括NK_细胞_静息,T细胞_CD4_记忆_静息,和巨噬细胞_M0。免疫检查点基因(CD274,SIGLEC15)在高PPAR表达组和低PPAR表达组之间异常表达。TTN,MUC16,FAT2和ANK3基因在高PPARA/PPARG和低PPARG表达组中都具有高突变频率。14种和两种PPARA/PPARD药物被确定能够有效治疗高PPARA/PPARG和低PPARA/PPARG表达组的患者,分别。我们还发现,化疗药物长春瑞滨与三个PPAR基因呈正相关,显示长春瑞滨作为STAD治疗药物的潜力。此外,细胞实验证明PPARG在AGS和SGC7901细胞中有较高的表达,抑制PPARG抑制了活力,AGS和SGC7901细胞的迁移和侵袭。
■目前的结果证实了三个PPAR基因(PPARA,PPARD和PPARG)通过介导免疫微环境和基因组突变影响STAD发育。
UNASSIGNED: Peroxisome proliferator-activated receptors (PPARs) exert multiple functions in the initiation and progression of stomach adenocarcinomas (STAD). This study analyzed the relationship between PPARs and the immune status, molecular mutations, and drug therapy in STAD.
UNASSIGNED: The expression profiles of three PPAR genes (PPARA, PPARD and PPARG) were downloaded from The Cancer Genome Atlas (TCGA) dataset to analyze their expression patterns across pan-cancer. The associations between PPARs and clinicopathologic features, prognosis, tumor microenvironment, genome mutation and drug sensitivity were also explored. Co-expression between two PPAR genes was calculated using Pearson analysis. Regulatory pathways of PPARs were scored using gene set variation analysis (GSVA) package. Quantitative real-time polymerase chain reaction (qRT-PCR), Western blot, Cell Counting Kit-8 (CCK-8) assay and transwell assay were conducted to analyze the expression and function of the PPAR genes in STAD cell lines (AGS and SGC7901 cells).
UNASSIGNED: PPARA, PPARD and PPARG were more abnormally expressed in STAD samples and cell lines when compared to most of 32 type cancers in TCGA. In STAD, the expression of PPARD was higher in Grade 3+4 and male patients, while that of PPARG was higher in patient with Grade 3+4 and age > 60. Patients in high-PPARA expression group tended to have longer survival time. Co-expression analysis revealed 6 genes significantly correlated with the three PPAR genes in STAD. Single-sample GSEA (ssGSEA) showed that the three PPAR genes were enriched in 23 pathways, including MITOTIC_SPINDLE, MYC_TARGETS_V1, E2F_TARGETS and were closely correlated with immune cells, including NK_cells_resting, T_cells_CD4_memory_resting, and macrophages_M0. Immune checkpoint genes (CD274, SIGLEC15) were abnormally expressed between high-PPAR expression and low-PPAR expression groups. TTN, MUC16, FAT2 and ANK3 genes had a high mutation frequency in both high-PPARA/PPARG and low-PPARA/PPARG expression group. Fourteen and two PPARA/PPARD drugs were identified to be able to effectively treat patients in high-PPARA/PPARG and low-PPARA/PPARG expression groups, respectively. We also found that the chemotherapy drug
Vinorelbine was positively correlated with the three PPAR genes, showing the potential of
Vinorelbine to serve as a treatment drug for STAD. Furthermore, cell experiments demonstrated that PPARG had higher expression in AGS and SGC7901 cells, and that inhibiting PPARG suppressed the viability, migration and invasion of AGS and SGC7901 cells.
UNASSIGNED: The current results confirmed that the three PPAR genes (PPARA, PPARD and PPARG) affected STAD development through mediating immune microenvironment and genome mutation.