Germline variation in <i>NCF4</i>, an innate immunity gene, is associated with an increased risk of colorectal cancer

Ryan, Bríd M.; Zanetti, Krista A.; Robles, Ana I.; Schetter, Aaron J.; Goodman, Julie E.; Hayes, Richard B.; Huang, Wen‐Yi; Gunter, Marc J.; Yeager, Meredith; Burdette, Laurie; Berndt, Sonja I.; Harris, Curtis C.

doi:10.1002/ijc.28457

Cited by 56 publications

(43 citation statements)

References 49 publications

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“…We evaluated in silico the correlation between CaSR expression and a signature of EMT markers using data available from the GEO database. This study by Ryan and colleagues [ 26 ] deposited microarray data from 111 tumor and adjacent mucosa samples from CRC patient samples.…”

Section: Resultsmentioning

confidence: 99%

The calcium-sensing receptor suppresses epithelial-to-mesenchymal transition and stem cell- like phenotype in the colon

et al. 2015

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BackgroundThe calcium sensing receptor (CaSR), a calcium-binding G protein-coupled receptor is expressed also in tissues not directly involved in calcium homeostasis like the colon. We have previously reported that CaSR expression is down-regulated in colorectal cancer (CRC) and that loss of CaSR provides growth advantage to transformed cells. However, detailed mechanisms underlying these processes are largely unknown.Methods and resultsIn a cohort of 111 CRC patients, we found significant inverse correlation between CaSR expression and markers of epithelial-to-mesenchymal transition (EMT), a process involved in tumor development in CRC. The colon of CaSR/PTH double-knockout, as well as the intestine-specific CaSR knockout mice showed significantly increased expression of markers involved in the EMT process. In vitro, stable expression of the CaSR (HT29CaSR) gave a more epithelial-like morphology to HT29 colon cancer cells with increased levels of E-Cadherin compared with control cells (HT29EMP). The HT29CaSR cells had reduced invasive potential, which was attributed to the inhibition of the Wnt/β-catenin pathway as measured by a decrease in nuclear translocation of β-catenin and transcriptional regulation of genes like GSK-3β and Cyclin D1. Expression of a spectrum of different mesenchymal markers was significantly down-regulated in HT29CaSR cells. The CaSR was able to block upregulation of mesenchymal markers even in an EMT-inducing environment. Moreover, overexpression of the CaSR led to down-regulation of stem cell-like phenotype.ConclusionsThe results from this study demonstrate that the CaSR inhibits epithelial-to-mesenchymal transition and the acquisition of a stem cell-like phenotype in the colon of mice lacking the CaSR as well as colorectal cancer cells, identifying the CaSR as a key molecule in preventing tumor progression. Our results support the rationale to develop new strategies either preventing CaSR loss or reversing its silencing.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-015-0330-4) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

The calcium-sensing receptor suppresses epithelial-to-mesenchymal transition and stem cell- like phenotype in the colon

et al. 2015

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“…CRC gene expression microarray data used in this study were downloaded from the publicly available GEO databases (http://www.ncbi.nlm.nih. gov/geo/): GSE21815 (20), GSE44076 (21), GSE44861 (22), GSE41258 (23) and GSE33113 (24). The GEO datasets used in this study include 562 CRC tissues and 222 NST from respective same patient groups.…”

Section: Gene Expression Databases and Cluster Analysis Gene Expressmentioning

confidence: 99%

Altered mRNA expression levels of the major components of sphingolipid metabolism, ceramide synthases and their clinical implication in colorectal cancer

Jang

Park

Min³

et al. 2018

Oncol Rep

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Ceramide synthases (CerSs) synthesize various ceramides of different acyl chain lengths and serve important roles in the proliferation and death of cancer cells by regulating sphingolipid metabolism-related signaling pathways. The present study investigated the mRNA expression levels of various CerS genes using mRNA expression data from six independent colorectal cancer (CRC) cohorts and a Korean CRC dataset. Expression levels of CERS2, CERS5 and CERS6 mRNA were significantly increased in the majority of the studied groups. However, CERS4 expression was only significantly altered in two groups. Additionally, a positive correlation was observed between altered CERS4 and CERS5 mRNA levels in The Cancer Genome Atlas Colon and Rectal Cancer dataset. Notably, CERS2 and CERS4, as well as CERS5 and CERS6 levels, were positively correlated with each other in Korean patients with CRC. However, the mRNA expression levels of these four CerS genes were not associated with any clinicopathological characteristics in Korean patients with CRC. Finally, overexpressing CERS2 or CERS6 inhibited the in vitro viability of various CRC cells. Taken together, these findings indicated that CERS2, CERS4, CERS5, and CERS6 are significantly dysregulated in CRC, suggesting they may serve important roles in the pathophysiology of this malignancy.

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“…mRNA microarray datasets GSE81582 [ 8 ], GSE44076 [ 9 ], and GSE44861 [ 10 ] and microRNA datasets GSE41655 [ 11 ] and GSE18392 [ 12 ] were downloaded from the Gene Expression Omnibus database (GEO DataSets). A total of 385 CRC samples and 206 normal control samples were collected from these datasets.…”

Section: Methodsmentioning

confidence: 99%

Identification and Interaction Analysis of Molecular Markers in Colorectal Cancer by Integrated Bioinformatics Analysis

Han

Feng

Yu³

et al. 2018

Med Sci Monit

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BackgroundColorectal cancer (CRC) is an extremely common gastrointestinal malignancy.Material/MethodsThree mRNA and 2 microRNA microarray datasets were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) and microRNAs (DEMs) were obtained. The Database for Annotation, Visualization, and Integrated Discovery (DAVID) program was utilized to perform gene ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Protein–protein interaction (PPI) network analysis was performed with the Search Tool for the Retrieval of Interacting Genes (STRING) and Cytoscape and Molecular Complex Detection (MCODE). Kaplan-Meier curves were plotted to determine overall survival (OS) estimates. DEMs targets were predicted by miRWalk. Quantitative reverse transcription polymerase chain reaction (QRT-PCR) was utilized to detect the expression of genes and microRNAs.ResultsA total of 264 DEGs and 8 DEMs were obtained. GO analysis revealed that the DEGs were enriched in terms of cell structure, digestion, receptor binding, and extracellular material (ECM). KEGG pathway analysis showed that the DEGs were enriched in ECM interaction and mineral absorption. Additionally, a PPI network consisting of 181 nodes and 450 edges was established. Three modules with 38 high-degree hubs were extracted from the PPI network and found to be involved in pathways such as chemokine signaling. Five DEGs located in the network of DEM-DEG pairs were associated with the overall survival of CRC patients. Furthermore, hsa-miR-551b was demonstrated to be significantly down-regulated in CRC tissues.ConclusionsThe key biomarkers could provide new clues for CRC.

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Germline variation in NCF4, an innate immunity gene, is associated with an increased risk of colorectal cancer

Cited by 56 publications

References 49 publications

The calcium-sensing receptor suppresses epithelial-to-mesenchymal transition and stem cell- like phenotype in the colon

The calcium-sensing receptor suppresses epithelial-to-mesenchymal transition and stem cell- like phenotype in the colon

Altered mRNA expression levels of the major components of sphingolipid metabolism, ceramide synthases and their clinical implication in colorectal cancer

Identification and Interaction Analysis of Molecular Markers in Colorectal Cancer by Integrated Bioinformatics Analysis

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