Epigenetic alterations of CYLD promoter modulate its expression in gastric adenocarcinoma: A footprint of infections

Abstract

Gastric cancer (GC) is one of the most common causes of cancer-related death in the world, with multiple genetic and epigenetic alterations involved in disease development. CYLD tumor suppressor gene encodes a multifunctional deubiquitinase which negatively regulates various signaling pathways. Deregulation of this gene has been found in different types of cancer. This study aimed to evaluate for the first time the CpG island methylation pattern of CYLD gene promoter, and its expression level in gastric adenocarcinoma. CYLD messenger RNA expression and promoter methylation in 53 tumoral and their non-neoplastic counterpart tissues were assessed using quantitative polymerase chain reaction and bisulfite sequencing. Also, we investigated the impacts of the infectious agents including Helicobacter pylori (H. pylori), EBV, and CMV on CYLD expression and promoter methylation in GC. Results showed that the expression level of CYLD was downregulated in GC, and was significantly associated with gender (female), patient's age (<60), high grade, and no lymph-node metastasis (p = 0.001, 0.002, 0.03, and 0.003, respectively). Among the 31 analyzed CpG sites located in about 600 bp region within the promoter, two CpG sites were hypermethylated in GC tissues. We also found a significant inverse association between DNA promoter methylation and CYLD expression (p = 0.02). Furthermore, a direct association between H. pylori, EBV, and CMV infections with hypermethylation and reduced CYLD expression was observed (p = 0.04, 0.03, and 0.03, respectively). Our findings indicate that CYLD is downregulated in GC. Infectious agents may influence CYLD expression.

Helicobacter pylori-induced DNA Methylation as an Epigenetic Modulator of Gastric Cancer: Recent Outcomes and Future Direction

“…Deregulation of CYLD , a tumor suppressor gene, has been found in different types of cancer. Association between H. pylori infections with hypermethylation and reduced CYLD expression was observed in 10 out of 21 CagA-positive, H. pylori -infected tumor samples [60]. PTEN is another tumor suppressor gene, which serve important functions in apoptosis, cell cycle progression and cell proliferation.…”

Epigenetic profiling of MUTYH, KLF6, WNT1 and KLF4 genes in carcinogenesis and tumorigenesis of colorectal cancer

“…Epigenetics consist of DNA methylation, histone modification, histone acetylation, histone phosphorylation and also RNA remodeling which DNA methylation is the most important element [6][7][8][9][10][11][12]. Meanwhile, alongside with the investigation of epigenetics fluctuation in GI cancers, gene expression study must be added in order to have a better comparison and result [13][14][15][16][17][18][19][20].…”

The fluctuation of APC gene in WNT signaling with adenine deletion of adenomatous polyposis coli, is associated in colorectal cancer

“…By the way, the quality and quantity of extracted nucleic acids including DNA and RNA alongside compatible primers are of great importance. [30][31][32][33]…”