Abstract
In colorectal cancer (CRC), upregulation of the C-X-C motif chemokine receptor 4 (CXCR4) is correlated with metastasis and poor prognosis, highlighting the need to further elucidate CXCR4’s regulation in CRC. For the first time, DNA methylation and 5-hydroxymethylcytosine aberrations were investigated to better understand the epigenetic regulation of CXCR4 in CRC. CXCR4 expression levels were measured using qPCR and immunoblotting in normal colon tissues, primary colon cancer tissues and CRC cell lines. Publicly available RNA-seq and methylation data from The Cancer Genome Atlas (TCGA) were extracted from tumors from CRC patients. The DNA methylation status spanning CXCR4 gene was evaluated using combined bisulfite restriction analysis (COBRA). The methylation status in the CXCR4 gene body was analyzed using previously performed nano-hmC-seal data from colon cancers and adjacent normal colonic mucosa. CXCR4 expression levels were significantly increased in tumor stromal cells and in tumor colonocytes, compared to matched cell types from adjacent normal-appearing mucosa. CXCR4 promoter methylation was detected in a minority of colorectal tumors in the TCGA. The CpG island of the CXCR4 promoter showed increased methylation in three of four CRC cell lines. CXCR4 protein expression differences were also notable between microsatellite stable (MSS) and microsatellite instable (MSI) tumor cell lines. While differential methylation was not detected in CXCR4, enrichment of 5-hydroxymethylcytosine (5hmC) in CXCR4 gene bodies in CRC was observed compared to adjacent mucosa.
Highlights
C-X-C motif chemokine ligand 12 (CXCL12), and its cognate receptor C-X-C motif chemokine receptor 4 (CXCR4), constitutes a major cytokine-signaling pathway involved in both health and disease [1,2]
In upregulated in metastatic tissue of the liver and lymph nodes compared to primary colorectal cancer (CRC) tumors the prior studies, it was not determined if CXCR4 overexpression correlated with CXCR4 in tumor
To extend our in colorectal cancer, we separated colonocytes from stromal cells and examined their CXCR4 expression understanding of CXCR4 regulation in colorectal cancer, we separated colonocytes from stromal levels compared to their control counterparts
Summary
C-X-C motif chemokine ligand 12 (CXCL12), and its cognate receptor C-X-C motif chemokine receptor 4 (CXCR4), constitutes a major cytokine-signaling pathway involved in both health and disease [1,2]. CXCR4 overexpression promotes tumorigenesis and its expression and activity are associated with cell proliferation [4,5,6,7,8], invasion [8,9,10,11,12,13], migration [8,14,15,16,17,18,19,20], inflammation [21], angiogenesis [22], and metastasis [23,24,25,26,27,28,29,30] in several cancer models. In the case of CRC patients, a meta-analysis correlated high CXCR4 expression with liver and lymph node metastasis and a reduction in overall survival [38]
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