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WGCNA identification of TLR7 as a novel diagnostic biomarker, progression and prognostic indicator, and immunotherapeutic target for stomach adenocarcinoma.

ABSTRACT: Stomach adenocarcinoma (STAD) is a malignant tumor with high histological heterogeneity. However, the potential mechanism of STAD tumorigenesis remains to be elucidated. The purpose of our research was to identify candidate genes associated with the diagnosis, progression, prognosis, and immunotherapeutic targets of STAD. Based on tumor samples from the GSE28541 dataset, weighted gene co-expression network analysis revealed 16 modules related to STAD stage and grade. The salmon module emerged as the most relevant module (cor = 0.34), and functional enrichment analysis showed that the genes in the salmon were primarily related to major histocompatibility complex, immune response, and cell differentiation. Toll-like receptor 7 (TLR7) was recognized as the real hub gene in the salmon module. Compared to normal stomach tissues, the transcriptional and translational levels of TLR7 were significantly elevated in STAD. Receiver operating characteristic curves verified that TLR7 displayed remarkable sensitivity and specificity for the diagnosis of STAD. The functions of TLR7 were primarily enriched in the regulation of Toll-like receptor signaling pathway, pattern recognition receptor signaling pathway, and innate immune response. Overexpression of TLR7 tended to indicate more advanced STAD, higher degree of STAD, and poorer prognosis of STAD. In addition, TLR7 expression was positively correlated with immune cell infiltration and immune checkpoint expression. Somatic copy number alteration of TLR7 was also significantly related to immune cell infiltration. In conclusion, this study revealed the crucial role of TLR7 in STAD and provided new perspectives for the selection of biomarkers, progression and prognosis indicators, and immunotherapeutic targets for STAD.

SUBMITTER: Yuan Q

PROVIDER: S-EPMC8209604 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The peroxisome serves a significant role in the occurrence and development of cancers. Specifically, the peroxisomal biogenesis factor 13 (PEX13) is crucial to the occurrence of peroxisomes. However, the biological function of PEX13 in cancers remains unclear. To address this, various portals and databases such as The Cancer Genome Atlas Program, The Genotype-Tissue Expression project, the Gene Expression Profiling Interactive Analysis 2, cBioPortal, the Genomic Identification of Significant Targets In Cancer 2.0, Tumor Immune Estimation Resource 2, SangerBox, LinkedOmics, DAVID and STRING were applied to extract and analyze PEX13 data in tumors. The correlations between PEX13 and prognosis, genetic alterations, PEX13-related gene enrichment analysis, weighted gene co-expression network analysis (WGCNA), protein interaction, long non-coding (lnc)RNA/circular (circ)RNA-micro (mi)RNA network and tumor immunity were explored in various tumors. The lncRNA-miRNA-PEX13 and circRNA-miRNA-PEX13 regulatory networks were identified via miRabel, miRDB, TargetScan and ENCORI portals and Cytoscape tool. In vitro assays were applied to verify the biological functions of PEX13 in pancreatic adenocarcinoma (PAAD) cells. The findings revealed that PEX13 is upregulated in various tumors and high PEX13 mRNA expression is associated with poor prognosis in patients with multiple cancers. Genetic alterations in PEX13 such as amplification, mutation and deep deletion have been found in multiple cancers. PEX13-related genes were associated with T cell receptor, signaling pathway and hippo signaling pathway through 'biological process' subontology of Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. Through WGCNA analysis, it was discovered that PEX13 hub genes were mainly enriched in the Rap1, ErbB and AMPK signaling pathways in PAAD. Immune analysis showed that PEX13 was significantly related to tumor infiltration immune cells, immune checkpoint genes, microsatellite instability, TMB and tumor purity in a variety of tumors. Cell Counting Kit-8, wound healing, Transwell and colony formation assays displayed that PEX13 knockdown could suppress PAAD cell proliferation, migration, invasion, and colony formation in vitro, respectively. Overall, PEX13 is a potential predictor of immunotherapeutic and prognostic biomarkers in various malignant tumors, including ACC, KICH, LGG, LIHC and PAAD.

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WGCNA identification of TLR7 as a novel diagnostic biomarker, progression and prognostic indicator, and immunotherapeutic target for stomach adenocarcinoma.

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