Abstract
By allelotyping for loss of heterozygosity (LOH), we previously identified a deletion region that harbors the candidate tumor suppressor gene DAL-1 at 18p11.3 in sporadic gastric cancers (GCs). The expression and function of DAL-1 in GCs remained unclear. Here, we demonstrated that the absence of or notable decreases in the expression of DAL-1 mRNA and protein was highly correlated with CpG hypermethylation of the DAL-1 promoter in primary GC tissues and in GC cell lines. Furthermore, abnormal DAL-1 subcellular localization was also observed in GC cells. Exogenous DAL-1 effectively inhibited cancer cell proliferation, migration, invasion and epithelial to mesenchymal transition (EMT); exogenous DAL-1 also promoted apoptosis in GC AGS cells. When endogenous DAL-1 was knocked down in GC HGC-27 cells, the cells appeared highly aggressive. Taken together, these findings provide solid evidence that aberrant expression of DAL-1 by hypermethylation in the promoter region results in tumor suppressor gene behavior that plays important roles in the malignancy of GCs. Understanding the role of it played in the molecular pathogenesis of GC, DAL-1 might be a potential biomarker for molecular diagnosis and evaluation of the GC.
Highlights
Gastric cancer (GC) is the fifth most common cancer in the world, nearly 1.0 million new cases were diagnosed in 2012
To evaluate the expression of differentially expressed in adenocarcinoma of the lung-1 (DAL-1) in gastric carcinogenesis, we initially analyzed the expression of DAL-1 mRNA and protein in surgically resected GC samples and adjacent noncancerous tissues from the same patients using Reverse transcriptase-polymerase chain reaction (RT-PCR) and IHC methods
RT-PCR results demonstrated that DAL-1 mRNA expression was reduced in 13 of 19 (68.4%) primary GC samples (Fig. 1a, Supplementary Table 1)
Summary
Gastric cancer (GC) is the fifth most common cancer in the world, nearly 1.0 million new cases were diagnosed in 2012. DAL-1 methylation in renal, lung, and breast cancers and in nasal NK/T-cell lymphoma was found to be associated with the downregulation of DAL-1 expression. Methylation has been shown to be an important mechanism of transcriptional silencing of this gene in these cancers[6,10,11,12] These findings indicate that DAL-1 is a candidate tumor suppressor gene and may serve as a target for inactivation in carcinogenesis. DAL-1 directly interacts with tumor suppressor in lung cancer 1 (TSLC1), whose juxtamembrane portion acts as a 4.1-binding motif. Both DAL-1 and TSLC1 are spectrin-actin-binding proteins. We demonstrated through functional analyses that the aberrant expression of DAL-1 is associated with malignancy in GC cells
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