Epigenetic alterations of CYLD promoter modulate its expression in gastric adenocarcinoma: A footprint of infections |
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Authors: | Elham Ghadami Novin Nikbakhsh Sadegh Fattahi Mohadeseh Kosari-Monfared Mohammad Ranaee Hassan Taheri Fatemeh Amjadi-Moheb Gholamali Godazandeh Shahryar Shafaei Anahita Nosrati Maryam Pilehchian Langroudi Ali Akbar Samadani Galia Amirbozorgi Vahideh Mirnia Haleh Akhavan-Niaki |
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Affiliation: | 1. Department of Genetics, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran;2. Department of Surgery, Rouhani Hospital, Babol University of Medical Sciences, Babol, Iran;3. Department of Genetics, Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran;4. Department of Pathology, Rouhani Hospital, Babol University of Medical Sciences, Babol, Iran;5. Department of Internal Medicine, Rouhani Hospital, Babol University of Medical Sciences, Babol, Iran;6. Department of Thoracic Surgery, Imam Khomeini Hospital, Mazandaran University of Medical Sciences, Sari, Iran;7. Department of Pathology, Imam Khomeini Hospital, Mazandaran University of Medical Sciences, Sari, Iran;8. Department of Genetics, Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran Department of Genetics, Gastrointestinal and Liver Diseases Research Center (GLDRC), Guilan University of Medical Sciences, Rasht, Iran;9. Department of Molecular Biology, North Research Center of Pasteur Institute, Amol, Iran;10. Faculty of Paramedicine, Babol University of Medical Sciences, Babol, Iran |
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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. |
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Keywords: | CYLD gastric cancer gene expression promoter methylation |
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