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Myosin Ia (MYO1A) has been shown to be frequently mutated in
colorectal tumors with
microsatellite instability (MSI) and to have
tumor suppressor activity in intestinal
tumors. Here, we investigated the frequency of frameshift mutations in the A8 microsatellite in exon 28 of MYO1A in MSI gastric and endometrial
tumors and found a high mutation rate in gastric (22/47; 46.8%) but not endometrial (3/48; 6.2%)
tumors. Using a regression model, we show that MYO1A mutations are likely to confer a growth advantage to gastric, but not endometrial
tumors. The mutant MYO1A(7A)
protein was shown to lose its membrane localization in
gastric cancer cells and a
cycloheximide-chase assay demonstrated that the mutant MYO1A(7A)
protein has reduced stability compared to the wild type MYO1A. Frequent MYO1A promoter hypermethylation was also found in gastric
tumors. Promoter methylation negatively correlates with MYO1A
mRNA expression in a series of 58 non-MSI gastric primary
tumors (Pearson's r = -0.46; p = 0.0003) but not in a cohort of 54 non-MSI endometrial
tumors and treatment of
gastric cancer cells showing high MYO1A promoter methylation with the demethylating agent
5-aza-2'-deoxycytidine, resulted in a significant increase of MYO1A
mRNA levels. We found that normal gastric epithelial cells, but not normal endometrial cells, express high levels of MYO1A. Therefore, when considered together, our findings suggest that MYO1A has
tumor suppressor activity in the normal gastric epithelium but not in the normal endometrium and inactivation of MYO1A either genetically or epigenetically may confer gastric epithelial cells a growth advantage.