Brush border myosin Ia inactivation in gastric but not endometrial tumors

Rocco Mazzolini, Paulo Rodrigues, Sarah Bazzocco, Higinio Dopeso, Ana M. Ferreira, Silvia Mateo-Lozano, Elena Andretta, Stefan M. Woerner, Hafid Alazzouzi, Stefania Landolfi, Javier Hernandez-Losa, Irati MacAya, Hiromu Suzuki, Santiago Ramõn Y Cajal, Mark S. Mooseker, John M. Mariadason, Johannes Gebert, Robert M.W. Hofstra, Jaume Reventõs, Hiroyuki YamamotoSimo Schwartz, Diego Arango

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15 Citations (Scopus)

Abstract

Brush border 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 MYO1A7A protein was shown to lose its membrane localization in gastric cancer cells and a cycloheximide-chase assay demonstrated that the mutant MYO1A7A 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. What's new? Brushborder myosin 1A (MYO1A), a monomeric ATP-dependent motor protein, was recently associated with tumor suppressor activity in the colon. Here, the authors demonstrate that MYO1A is one of the most frequently mutated genes (47%) in gastric tumors with microsatellite instability (MSI). Moreover, the promoter of MYO1A was found frequently methylated. This was unique to gastric tumors, as only background mutation rates in MYO1A (6%) were observed in endometrial tumors with MSI, highlighting profound differences in the tumorigenic processes of these organs. Copyright © 2012 UICC.
Original languageEnglish
Pages (from-to)1790-1799
JournalInternational Journal of Cancer
Volume132
Issue number8
DOIs
Publication statusPublished - 15 Apr 2013

Keywords

  • endometrial cancer
  • gastric cancer
  • methylation
  • MSI
  • MYO1A

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