Tumor‑induced DNA methylation in the white blood cells of patients with colorectal cancer

Abstract

The secretions of cancer cells alter epigenetic regulation in cancer stromal cells. The present study investigated the methylation changes in white blood cells (WBCs) caused by the secretions of colorectal cancer (CRC) cells. Changes in the DNA methylation of peripheral blood mononuclear cells (PBMCs) from normal individuals co-cultured with CRC cells were estimated using a methylation microarray. These changes were then compared against the DNA methylation changes and mRNA levels observed in the WBCs of patients with CRC. Procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1 ( PLOD1 ) and matrix metalloproteinase 9 ( MMP9 ) were selected to assess the DNA methylation of the WBCs from CRC patients using real-time methylation-specific PCR. The majority of the genes analyzed presented high levels of mRNA in the WBCs of the patients with CRC and DNA methylation in the co-cultured PBMCs. Intragenic methylation revealed the strongest association (P=8.52×10 −21 ). For validation, MMP9 and PLOD1 were selected and used to test WBCs from 32 patients with CRC and 57 normal controls. The intragenic MMP9 methylation was commonly found (P<0.0001) with high sensitivity (90.63%) and high specificity (96.49%), and a positive predictive value of 93.33% and a negative predictive value of 93.22%. PLOD1 methylation was revealed to have lower sensitivity (30.00%) but higher specificity (97.92%). In addition to circulating WBCs, MMP9 protein expression was observed in infiltrating WBCs and the metastatic lymph nodes of patients with CRC. In conclusion, CRC cells secrete factors that induce genome wide DNA methylation changes in the WBCs of patients with CRC. These changes, including intragenic MMP9 methylation in WBCs, are promising CRC biomarkers to be tested in future CRC screening studies.

Differential Expression of Immune-Regulatory Protein C5AR1, NLRP3 and CLEC4A on Peripheral Blood Mononuclear Cells in Early-Stage Non-Small Cell Lung Cancer Patients

“…Previous studies from our group reported paracrine signal-induced PBMC gene upregulation in various cancer types through epigenetic regulation (4,16,17). On the basis of paracrine signal-induced PBMC gene upregulation, we explored the possibility to use protein expression on circulating T-lymphocytes as a biomarker to discriminate early-stage NSCLC and healthy individuals by automated ow cytometry analysis.…”

“…Expression of immune-related molecules on peripheral blood mononuclear cell (PBMC) is considered to play a role in antitumor activity. The changes of gene expression pro ling in PBMC seem to represent the host's response to the cancer cells via paracrine signal (4). Several studies have shown that the characterization of gene expression in PBMC may be useful as a diagnostic or for early detection (5)(6)(7).…”

Comprehensive analysis of PLOD family members in low-grade gliomas using bioinformatics methods

“…bladder cancer [33][34][35][36]. Moreover, previous research has presented that the expression PLOD1 can be predicted prognosis of IDH mut glioma patients, which involved in oxygen metabolism [37].…”

Comprehensive Analysis of PLOD Family Members in Low-grade Gliomas Using Bioinformatics Methods

“…PLOD1 has been reported that its aberrant expression level was signi cantly correlated with various human cancers, including prostate cancer, gastric cancer, colorectal cancer and bladder cancer [32][33][34][35].…”