Abstract
BackgroundClaudins are membrane proteins that play critical roles in tight junction (TJ) formation and function. Members of the claudin gene family have been demonstrated to be aberrantly regulated, and to participate in the pathogenesis of various human cancers. In the present study, we report that claudin-11 (CLDN11) is silenced in gastric cancer via hypermethylation of its promoter region.Methodology/Principal FindingsLevels of CLDN11 methylation and mRNA expression were measured in primary gastric cancer tissues, noncancerous gastric mucosae, and cell lines of gastric origin using quantitative methylation-specific PCR (qMSP) and quantitative reverse transcriptase-PCR (qRT-PCR), respectively. Analyses of paired gastric cancers and adjacent normal gastric tissues revealed hypermethylation of the CLDN11 promoter region in gastric cancers, and this hypermethylation was significantly correlated with downregulation of CLDN11 expression vs. normal tissues. The CLDN11 promoter region was also hypermethylated in all gastric cancer cell lines tested relative to immortalized normal gastric epithelial cells. Moreover, CLDN11 mRNA expression was inversely correlated with its methylation level. Treatment of CLDN11-nonexpressing gastric cancer cells with 5-aza-2′-deoxycytidine restored CLDN11 expression. Moreover, siRNA-mediated knockdown of CLDN11 expression in normal gastric epithelial cells increased their motility and invasiveness.Conclusions/SignificanceThese data suggest that hypermethylation of CLDN11, leading to downregulated expression, contributes to gastric carcinogenesis by increasing cellular motility and invasiveness. A further understanding of the mechanisms underlying the role of claudin proteins in gastric carcinogenesis will likely help in the identification of novel approaches for diagnosis and therapy of gastric cancer.
Highlights
Gastric cancer (GC) remains the second most-common cause of cancer deaths globally
Paired primary gastric normal and tumor tissues were collected at the Johns Hopkins Hospital (JHH)
We first tested our hypothesis that the CLDN11 promoter is hypermethylated and that this hypermethylation correlates inversely with CLDN11 mRNA expression in primary GC tissues
Summary
Gastric cancer (GC) remains the second most-common cause of cancer deaths globally. It is one of the most lethal malignancies and a leading cause of cancer deaths in developing countries, with overall 5-year survival rates below 20% [1,2].Studies of GCs and their preneoplastic precursor lesions have identified several genetic and epigenetic alterations, including microsatellite instability, point mutations, and loss of heterozygosity (LOH) affecting tumor suppressor genes (TSGs) [3,4,5,6]. The current study identifies and reports, to our knowledge for the first time, that the CLDN11 promoter region is hypermethylated in GC tissues and cell lines. SiRNA-mediated downregulation of CLDN11 in CLDN11-expressing gastric cells was associated with cancer-related phenotypic changes, increased cell motility and invasiveness.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
