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Prognostic Value and the Immune Microenvironment-associated Role ofSMAD4in Pancreatic Adenocarcinoma

生物 免疫系统 CD8型 癌症研究 肿瘤微环境 胰腺癌 转录组 髓样 基因表达 免疫学 基因 癌症 遗传学
作者
Yang Song,Yuxuan Wang,Tianyu Yu,Yuan He,CHUNYAN WANG,Fuqiang Wang,Yixing Zhou
出处
期刊:Anticancer Research [Anticancer Research USA Inc.]
卷期号:43 (12): 5393-5408 被引量:1
标识
DOI:10.21873/anticanres.16743
摘要

SMAD4 is a well-known cancer suppressor gene that regulates cell proliferation, differentiation, autoimmunity, pluripotency, and immune responses in pancreatic adenocarcinoma (PAAD). We herein investigated a novel involvement of SMAD4 within the PAAD microenvironment.Transcriptome data, derived from The Cancer Genome Atlas and Genotype-Tissue Expression Using TIMER 2.0, CIBERSORT, and ImmuCellAI, were used to identify the immune cell infiltration pattern of PAAD. We then knocked-down SMAD4 in the PANC-1 cell line and acquired RNA-seq data through the Illumina microarray technology. Kyoto Encyclopedia of Genes and Genomes was utilized along with Gene Ontology enrichment analyses, and protein-protein interaction network analysis to screen for genes that were differentially expressed. We constructed a miRNA-mRNA regulatory network and analyzed SMAD4 copy number variation (CNV) data.In PAAD, decreased levels of SMAD4 expression were found to be connected to an unfavorable prognosis. There was a significantly higher infiltration level of DC cells, CD8+ T cells, TgD, Tc, and Tex cells and a lower level of B cells and Th2 in the SMAD4-high group. The expression of SMAD4 and immune cell infiltration including CD8+ T cells, myeloid dendritic cells, neutrophils, and macrophages are significantly positively correlated. DEGs were found enriched in the hypoxia response pathway. The six hypoxia-related genes exhibited a significant correlation with immune cell infiltration and survival rates. SMAD4 CNV levels were associated with MSI, stemness, infiltration of immune cells, and survival rates.A statistically significant correlation was found between SMAD4 expression and immune cell infiltration. SMAD4 could mediate hypoxia response in pancreatic cancer. The CNV levels of SMAD4 were associated with prognosis. SMAD4 has potential as a prognostic biomarker and provides a new orientation for the immunotherapy of PAAD.
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