ORIGINAL ARTICLE   

Gazzetta Medica Italiana - Archivio per le Scienze Mediche 2019 May;178(5):292-300

DOI: 10.23736/S0393-3660.18.03799-3

Copyright © 2018 EDIZIONI MINERVA MEDICA

lingua: Inglese

Decreased expression of the Keap1 gene and its clinicopathological significance in gastric cancer: correlation with promoter DNA methylation

Narges SOOZANGAR ^{1, 2, 3}, Mohammad R. SADEGHI ², Farhad JEDDI ³, Nasser SAMADI ^{2, 4}, Mohammad S. HEJAZI ², Mehdi AZAD ⁵, Masoud SHIRMOHAMADI ¹, Mohammad H. SOMI ^{1, 2} ✉

¹ Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; ² Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran; ³ Research Laboratory for Embryology and Stem Cells, Department of Anatomical Sciences and Pathology, School of Medicine, Ardabil University of Medical Sciences, Ardabil , Iran; ⁴ Department of Biochemistry, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran; ⁵ Department of Medical Laboratory Sciences, Faculty of Allied Medicine, Qazvin University of Medical Sciences, Qazvin, Iran

BACKGROUND: Kelch-like ECH-associated protein1 (Keap1) is a cytoplasmic anchor of nuclear factor erythroid 2-related factor2 (Nrf2), which mediates the regulation of genes involved in apoptosis and cell survival. Epigenetic events such as aberrant DNA methylation is emerging as a possible mechanism for dysregulation of the Keap1 in cancer. However, the impacts of Keap1 methylation and expression on gastric cancer (GC) development and progression have not yet been investigated.
METHODS: We analyzed the Keap1 promoter methylation and its mRNA or protein expression in endoscopic biopsies from 60 GC patients compared with those in non-GC individuals by methylated DNA immunoprecipitation (MeDIP) assay, quantitative real-time PCR and immunohistochemistry, respectively.
RESULTS: The methylation level of Keap1 in GC was remarkably higher than that in non-GC biopsies (P<0.001). In contrast, the mRNA and protein expression of Keap1 were clearly down-regulated in GC in comparison with the non-GC tissues (P<0.001). In addition, there were significant differences in both Keap1 methylation or expression levels between the low and high histological grade. Statistical analysis revealed that Keap1 expression inversely correlates to its promoter methylation in GC (r=-0.55, P<0.001).
CONCLUSIONS: Our results reflect an epigenetic regulation of Keap1 expression and highlight the importance of Keap1 downregulation and its promoter hypermethylation in GC pathogenesis.

KEY WORDS: Clinical pathology - DNA methylation - Stomach neoplasms - Kelch-like ECH-associated protein 1 - GA-binding protein transcription factor