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Abstract：
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an often fatal malignancy with an extremely low survival rate. Liver metastasis, which causes high mortality, is the most common recurring metastasis for PDAC. However, the mechanisms underlying this liver metastasis and associated candidate biomarkers are unknown.
METHODS: We performed mRNA profiling comparisons in 8 primary tumors (T) and 12 liver metastases (M) samples using the Gene Expression Omnibus (GEO) database. After determining differentially expressed genes (DEG), gene ontology (GO), pathway enrichment and protein-protein interaction (PPI) network analyses were performed to determine DEG functions. Then, Cytoscape was used to screen out significant hub genes, after which their clinical relevance was investigated using The Cancer Genome Atlas (TCGA) resources. Furthermore, prognosis-associated gene expression was validated using Oncomine and TCGA database. Lastly, associations between prognosis-associated genes, immune cells and immunological checkpoint genes were evaluated using the Tumor Immune Estimation Resource (TIMER).
RESULTS: In total, 102 genes were related to liver metastasis and predominantly involved in cell migration, motility, and adhesion. Using Cytoscape, this number was narrowed down to 16 hub genes. Elevated mRNA expression levels for two of these genes, SPARC (P = 0.019) and TPM1 (P = 0.037) were significantly correlated with poor disease prognosis. For the remaining 14, expression was not related to overall patient survival. SPARC had higher expression in patients with metastatic PDAC than those with non-metastatic PDAC in TCGA dataset. SPARC and TPM1 levels were also positively correlated with the immune infiltration of specific cell types. Additionally, both genes exhibited strong co-expression associations with immune checkpoint genes.
CONCLUSIONS: Combined, we suggest SPARC has high potential as biomarker to predict liver metastasis during PDAC. Additionally, both SPARC and TPM1 appeared to recruit and regulate immune-infiltrating cells during these pathophysiological processes.
METHODS: We performed mRNA profiling comparisons in 8 primary tumors (T) and 12 liver metastases (M) samples using the Gene Expression Omnibus (GEO) database. After determining differentially expressed genes (DEG), gene ontology (GO), pathway enrichment and protein-protein interaction (PPI) network analyses were performed to determine DEG functions. Then, Cytoscape was used to screen out significant hub genes, after which their clinical relevance was investigated using The Cancer Genome Atlas (TCGA) resources. Furthermore, prognosis-associated gene expression was validated using Oncomine and TCGA database. Lastly, associations between prognosis-associated genes, immune cells and immunological checkpoint genes were evaluated using the Tumor Immune Estimation Resource (TIMER).
RESULTS: In total, 102 genes were related to liver metastasis and predominantly involved in cell migration, motility, and adhesion. Using Cytoscape, this number was narrowed down to 16 hub genes. Elevated mRNA expression levels for two of these genes, SPARC (P = 0.019) and TPM1 (P = 0.037) were significantly correlated with poor disease prognosis. For the remaining 14, expression was not related to overall patient survival. SPARC had higher expression in patients with metastatic PDAC than those with non-metastatic PDAC in TCGA dataset. SPARC and TPM1 levels were also positively correlated with the immune infiltration of specific cell types. Additionally, both genes exhibited strong co-expression associations with immune checkpoint genes.
CONCLUSIONS: Combined, we suggest SPARC has high potential as biomarker to predict liver metastasis during PDAC. Additionally, both SPARC and TPM1 appeared to recruit and regulate immune-infiltrating cells during these pathophysiological processes.
摘要：
背景：胰腺导管腺癌（PDAC）是一种通常致命的恶性肿瘤，生存率极低。肝转移,导致高死亡率，是PDAC最常见的复发转移。然而,肝转移的潜在机制和相关候选生物标志物尚不清楚.
方法：我们使用基因表达综合（GEO）数据库在8个原发性肿瘤（T）和12个肝转移（M）样品中进行了mRNA谱分析比较。在确定差异表达基因（DEG）后，基因本体论(GO)，进行途径富集和蛋白质-蛋白质相互作用(PPI)网络分析以确定DEG功能.然后，Cytoscape被用来筛选重要的枢纽基因，之后，使用癌症基因组图谱（TCGA）资源研究了它们的临床相关性。此外，使用Oncomine和TCGA数据库验证预后相关基因表达。最后,预后相关基因之间的关联，使用肿瘤免疫评估资源(TIMER)评估免疫细胞和免疫检查点基因.
结果：总计，102个基因与肝转移相关，主要参与细胞迁移，运动性,和附着力。使用Cytoscape，这个数字缩小到16个hub基因。其中两个基因的mRNA表达水平升高，SPARC(P=0.019)和TPM1(P=0.037)与不良预后相关。对于剩余的14个,表达与患者的总体存活无关。在TCGA数据集中，转移性PDAC患者的SPARC表达高于非转移性PDAC患者。SPARC和TPM1水平也与特定细胞类型的免疫浸润呈正相关。此外,这两个基因均与免疫检查点基因表现出强烈的共表达关联.
结论：组合，我们建议SPARC作为预测PDAC期间肝转移的生物标志物具有很高的潜力.此外,在这些病理生理过程中,SPARC和TPM1似乎都能募集和调节免疫浸润细胞.
方法：我们使用基因表达综合（GEO）数据库在8个原发性肿瘤（T）和12个肝转移（M）样品中进行了mRNA谱分析比较。在确定差异表达基因（DEG）后，基因本体论(GO)，进行途径富集和蛋白质-蛋白质相互作用(PPI)网络分析以确定DEG功能.然后，Cytoscape被用来筛选重要的枢纽基因，之后，使用癌症基因组图谱（TCGA）资源研究了它们的临床相关性。此外，使用Oncomine和TCGA数据库验证预后相关基因表达。最后,预后相关基因之间的关联，使用肿瘤免疫评估资源(TIMER)评估免疫细胞和免疫检查点基因.
结果：总计，102个基因与肝转移相关，主要参与细胞迁移，运动性,和附着力。使用Cytoscape，这个数字缩小到16个hub基因。其中两个基因的mRNA表达水平升高，SPARC(P=0.019)和TPM1(P=0.037)与不良预后相关。对于剩余的14个,表达与患者的总体存活无关。在TCGA数据集中，转移性PDAC患者的SPARC表达高于非转移性PDAC患者。SPARC和TPM1水平也与特定细胞类型的免疫浸润呈正相关。此外,这两个基因均与免疫检查点基因表现出强烈的共表达关联.
结论：组合，我们建议SPARC作为预测PDAC期间肝转移的生物标志物具有很高的潜力.此外,在这些病理生理过程中,SPARC和TPM1似乎都能募集和调节免疫浸润细胞.
