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Comprehensive analysis for gene expressions of normal human dermal fibroblasts supplemented with N-acetylglucosamine -bearing polymers

ABSTRACT: To reveal the comprehensive gene expression of normal human dermal fibroblasts (NHDFs) based on the interaction of GlcNAc-bearing polymer, AC-GlcNAc10, with cell surface vimentin at 24 h, we performed a DNA microarray for NHDFs treated with AC-GlcNAc10. The DNA microarray analysis revealed altered expression of approximately 1000 genes in NHDF vs. NHDF treated with AC-GlcNAc10 by extracting differentially expressed genes with the ratio of >1.5 and <0.66-fold changes between the gene expressions of NHDF vs. NHDF treated with AC-GlcNAc10, and Z-score >2.0 and <-2.0. We observed the downregulation of gene expression related to cell cycle progression, such as baculoviral IAP repeat-containing protein 5 (BIRC5; survivin), and the upregulation of gene expression related to cell cycle arrest, such as cyclin-dependent kinase inhibitor 1A (CDKN1A; p21).

ORGANISM(S): Homo sapiens

PROVIDER: GSE199655 | GEO | 2022/03/30

REPOSITORIES: GEO

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Project description:Esophageal cancer is one of the most common cancers where TP53 is mutated frequently. Esophageal squamous cell carcinoma (ESCC) is the major subtype of esophageal cancer, and is one of the most lethal cancers worldwide. ESCC evolves often to lung metastasis, which is associated with a dismal prognosis. P53R175H (homologous to Trp53R172H in mice) is a common hot spot mutation. How metastasis is regulated by p53R175H in ESCC, or cancers in general, remains to be elucidated. To investigate p53R175H mediated molecular mechanisms, we utilized germline Trp53R172H/- mice, and generated esophageal specific Trp53-/- mice and Trp53+/+ mice treated with the 4-NQO esophageal-specific carcinogen (a common exposure in humans) to model ESCC. In the primary Trp53R172H/- tumor cell lines established from these mouse models, we depleted Trp53R172H (shTrp53) and observed a marked reduction in cell invasion in vitro and lung metastasis burden in a tail-vein injection model in comparing isogenic cells (shCtrl). Furthermore, to understand the molecular basis for mutant p53 driven lung metastasis, we performed bulk RNA-seq to compare gene expression profiles of metastatic and primary shCtrl and shTrp53 cells. We performed Gene Set Enrichment Analysis (GSEA) and identified the YAP-BIRC5 axis as a potential mediator of Trp53R172H mediated metastasis. As a target gene of YAP, BIRC5 encodes an anti-apoptotic protein, namely survivin. We demonstrate that survivin expression increases in the presence of Trp53R172H but not wild-type Trp53. Furthermore, depletion of survivin decreases Trp53R172H driven lung metastasis. Mechanistically, Trp53R172H but not wild-type Trp53, binds with YAP in ESCC cells, suggesting their cooperation to induce survivin expression. Furthermore, survivin high expression level is associated with increased metastasis in several GI cancer, suggesting that survivin may be a key regulator to metastasis. Taken together, this study unravels new insights into how mutant p53 mediates metastasis.

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Comprehensive analysis for gene expressions of normal human dermal fibroblasts supplemented with N-acetylglucosamine -bearing polymers

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