Dataset Information

Differential Expression of NEK Kinase Family Members in Esophageal Adenocarcinoma and Barrett's Esophagus.

ABSTRACT: The incidence of esophageal adenocarcinoma (EAC) has risen rapidly during the past four decades, making it the most common type of esophageal cancer in the USA and Western countries. The NEK (Never in mitosis A (NIMA) related kinase) gene family is a group of serine/threonine kinases with 11 members. Aberrant expression of NEKs has been recently found in a variety of human cancers and plays important roles in tumorigenesis, progression, and drug-resistance. However, the expression of the NEKs in EAC and its precancerous condition (Barrett's esophagus, BE) has not been investigated. In the present study, we first analyzed the TCGA and 9 GEO databases (a total of 10 databases in which 8 contain EAC and 6 contain BE) using bioinformatic approaches for NEKs expression in EAC and BE. We identified that several NEK members, such as NEK2 (7/8), NEK3 (6/8), and NEK6 (6/8), were significantly upregulated in EAC as compared to normal esophagus samples. Alternatively, NEK1 was downregulated in EAC as compared to the normal esophagus. On the contrary, genomic alterations of these NEKs are not frequent in EAC. We validated the above findings using qRT-PCR and the protein expression of NEKs in EAC cell lines using Western blotting and in primary EAC tissues using immunohistochemistry and immunofluorescence. Our data suggest that frequent upregulation of NEK2, NEK3, and NEK7 may be important in EAC.

SUBMITTER: Chen L

PROVIDER: S-EPMC10571661 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Differential Expression of NEK Kinase Family Members in Esophageal Adenocarcinoma and Barrett's Esophagus.

Chen Lei L Ballout Farah F Lu Heng H Hu Tianling T Zhu Shoumin S Chen Zheng Z Peng Dunfa D

Cancers 20230930 19

The incidence of esophageal adenocarcinoma (EAC) has risen rapidly during the past four decades, making it the most common type of esophageal cancer in the USA and Western countries. The NEK (Never in mitosis A (NIMA) related kinase) gene family is a group of serine/threonine kinases with 11 members. Aberrant expression of NEKs has been recently found in a variety of human cancers and plays important roles in tumorigenesis, progression, and drug-resistance. However, the expression of the NEKs in ...[more]

PMID: 37835513

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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.

Project description:As the premalignant lesion of human esophageal adenocarcinoma (EAC), Barrett's esophagus (BE) is characterized by intestinal metaplasia in the normal esophagus (NE). Gene expression profiling with microarray and serial analysis of gene expression (SAGE) may help us understand the potential molecular mechanism of human BE.We analyzed three microarray datasets (two cDNA arrays and one oligonucleotide array) and one SAGE dataset with statistical tools, significance analysis of microarrays (SAM) and SAGE(Poisson), to identify individual genes differentially expressed in BE. Gene set enrichment analysis (GSEA) was used to identify a priori defined sets of genes that were differentially expressed. These gene sets were grouped according to either certain signaling pathways (GSEA curated), or the presence of consensus binding sequences of known transcription factors (GSEA motif). Immunohistochemical staining (IHC) was used to validate differential gene expression.Both SAM and SAGE(Poisson) identified 68 differentially expressed genes (55 BE genes and 13 NE genes) with an arbitrary cutoff ratio (> or =4-fold). With IHC on matched pairs of NE and BE tissues from 6 patients, these genes were grouped into 6 categories: category I (25 genes only expressed in BE), category II (5 genes only expressed in NE), category III (8 genes expressed more in BE than in NE), and category IV (2 genes expressed more in NE than in BE). Differential expression of the remaining genes was not confirmed by IHC either due to false discovery (category V), or lack of proper antibodies (category VI). Besides individual genes, the TGFbeta pathway and several transcription factors (CDX2, HNF1, and HNF4) were identified by GSEA as enriched pathways and motifs in BE. Apart from 9 target genes known to be up-regulated in BE, IHC staining confirmed up-regulation of 19 additional CDX1 and CDX2 target genes in BE.Our data suggested an important role of CDX1 and CDX2 in the development of BE. The IHC-confirmed gene list will lead to future studies on the molecular mechanism of BE.

Dataset Information

Differential Expression of NEK Kinase Family Members in Esophageal Adenocarcinoma and Barrett's Esophagus.

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Differential Expression of NEK Kinase Family Members in Esophageal Adenocarcinoma and Barrett's Esophagus.

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