Brush border myosin Ia inactivation in gastric but not endometrial tumors

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 MYO1A 7Aprotein 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 5 20.46; p 5 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 0 -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.

Non‐muscle myosins in tumor progression, cancer cell invasion, and metastasis

“…In patients with colorectal cancer, lower level of Myo1a expression was associated with faster tumor progression and poor prognosis [Mazzolini et al, ]. Similar findings (enhanced mutation frequency and promoter hypermethylation of MYO1A ) were observed in patients with gastric tumors [Mazzolini et al, ]. Thus, several lines of evidence point to Myo1a serving as an important tumor suppressor in colorectal cancers both in vitro and in vivo and loss of Myo1a function may also serve as a prognostic indicator in colorectal and gastric cancer.…”

Down-regulated and Commonly mutated ALPK1 in Lung and Colorectal Cancers

“…It was previously reported that myosin Ia possesses the capacity for tumor suppression through its regulation of the polarization and differentiation of colorectal cancers16. In previous reports, α-kinase 1 (ALPK1), one of the components of the apical transport machinery, has been identified as an important source for modulating polarized trafficking in enterocytes, and high expression levels of ALPK1 have been found to promote myosin Ia phosphorylation and regulation in epithelial cell differentiation and polarization7.…”

“…Nevertheless, cancer development is actually a multistep process, during which the trait of malignant growth is formed in transformed cells, including insensitivity to antigrowth signals, unregulated proliferation potential, enhanced angiogenesis, metastasis, and so on16. The lower expression of ALPK1 in the tumor tissue samples of cancer patients implied that the disturbance of cell space polarization due to the reduction of ALPK1 expression might contribute to the initiation of tumorigenesis.…”

Aberrant Myosin 1b Expression Promotes Cell Migration and Lymph Node Metastasis of HNSCC

“…The roles of myosin family motor proteins in cancer cell characteristics have not yet been well-investigated (34,40,41) although the role of myosin family motor proteins-particularly myosin 2-in cancer motility through cross-linking actin filaments has previously been reported (42,43). In this article, we have revealed that aberrant overexpression of Myo1b in human HNSCC enhanced lymph node metastasis, possibly through increased cell motility and that Myo1b may be an attractive molecule for the development of new diagnostic and therapeutic strategies for patients with HNSCC.…”