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Gene expression profile for NGAL overexpression in esophageal squamous carcinoma cell

ABSTRACT: Neutrophil gelatinase associated lipocalin (NGAL), also known as oncogene 24p3, uterocalin, siderocalin or lipocalin 2 (Lcn2), is a member of the lipocalin family. Elevated NGAL involves various functions in malignant cells, even sometimes the conclusions were controversial. NGAL inhibits apoptosis in thyroid cancer and decrease invasion and angiogenesis in pancreatic cancer, but it increase proliferation and metastasis in breast and colon cancer. Nonetheless, the molecular functions and mechanisms of NGAL in ESCC are unknown. To address these issues and to identify genes and biological pathways associated with NGAL functions and mechanism, NGAL was overexpressed by pcDNA3.0 plasmid in ESCC cell line EC109 with an empty plasmid as a control, these two cells were applied for mRNA expression profile analyses to find the differentially expressed genes. Plasmids of pcDNA3.0-NGAL and pcDNA3.0 were transfected into ESCC cell line EC109, respectively. Stable transfected cell clones were selected by G418. The overexpression of NGAL protein was confirmed by western blot. Total RNAs from NGAL overexpressed cells and control cells were extracted for Agilent whole genome oligo microarray. A dye flip was performed for duplicate.

ORGANISM(S): Homo sapiens

SUBMITTER: Li Enmin

PROVIDER: S-ECPF-GEOD-57630 | biostudies-other |

REPOSITORIES: biostudies-other

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Project description:To uncover the genes associated with the development of esophageal squamous cell carcinoma (ESCC), an ESCC microarray dataset was used to identify genes differentially expressed between ESCC and normal control tissues. The dataset GSE17351 was downloaded from the Gene Expression Omnibus, containing 5 tumor esophageal mucosa samples and 5 adjacent normal esophageal mucosa samples from 5 male patients with ESCC. The differentially expressed genes (DEGs) were identified using the Linear Models for Microarray Data R package. Then, a co-expression network was constructed using the Weighted Correlation Network Analysis (WGCNA) package, and co-expression network modules were obtained with a hierarchical clustering algorithm. Additionally, functional enrichment analyses for DEGs in the top 2 modules with the highest significance were respectively conducted using the WGCNA package and the cluster Profiler package. In total, 487 upregulated and 468 downregulated DEGs were identified. A total of 24 modules were obtained from the co-expression network, and the top 2 modules with the highest significance, designated as 'blue4' and 'magenta', were further analyzed. In the module blue4, DEGs were significantly enriched in a number of Gene Ontology terms, including 'spindle organization' [e.g., ubiquitin conjugating enzyme E2 C (UBE2C) and SAC3 domain containing 1] and 'cell cycle process' [e.g., UBE2C, minichromosome maintenance complex component 6 (MCM6) and cell division cycle 20 (CDC20)]. Furthermore, a number of DEGs (e.g., UBE2C, CDC20 and MCM6) were enriched in the 'cell cycle' and 'ubiquitin mediated proteolysis' pathways. In the module 'magenta', a number of DEGs [e.g., transferrin receptor (TFRC) and TEA domain transcription factor 4 (TEAD4)] were enriched in the primary metabolic process and intracellular membrane-bounded organelle. Additionally, 308 upregulated genes and 215 downregulated genes were differentially expressed in the same pattern in another dataset, GSE20347, including UBE2C, CDC20, MCM6, TFRC, TEAD4, protein phosphatase 1 regulatory subunit 3C and MAL, T-cell differentiation protein. These DEGs may function in the development of ESCC.

Project description:Esophageal adenocarcinoma (EAC) is strongly associated with Barrett's esophagus (BE), a pre-malignant condition resulting from gastric reflux. Esophageal squamous cell carcinoma (ESCC), the other major subtype of esophageal cancer, shows strong association with smoking and alcohol intake and no association with gastric reflux. In this study, we constructed and validated gene expression signatures of EAC vs. ESCC tumors using publicly available datasets, and subsequently assessed the enrichment levels of these signatures in commonly used EAC and ESCC cell lines, normal esophageal tissues and normal esophageal cell lines, and primary BE tissues and BE cell lines. We found that unlike ESCC cell lines which were quite similar to primary ESCC tumors, EAC cell lines were considerably different from primary EAC tumors but still more similar to EAC tumors than ESCC tumors, as the genes up in EAC vs. ESCC (EAChi) had considerably lower expression in EAC cell lines than EAC tumors. However, more surprisingly, unlike various normal cell lines (EPC2, Het-1A) which were very similar to various tissues from normal esophagus, BE cell lines (BAR-T, CP-A) were extremely different from primary BE tissues, as BE cell lines had substantially lower levels of EAChi and substantially higher levels of ESCChi gene expression. This ESCC-like profile of the BAR-T remained unaltered even after prolonged exposure to an acidic bile mixture in vitro resulting in malignant transformation of this cell line. However, primary BE tissues had EAC-like gene expression profiles as expected. Only one EAC case from the Cancer Genome Atlas resembled BE cell lines, and while it had the clinical profile and some mutational features of EAC, it had some mutational features, the copy number alteration profile, and the gene expression profile of ESCC instead. These incomprehensible changes in gene expression patterns may result in ambiguous changes in the phenotype and warrants careful evaluation to inform selection of appropriate in vitro tools for future studies on esophageal adenocarcinoma.

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Gene expression profile for NGAL overexpression in esophageal squamous carcinoma cell

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