Ezrin overexpression in gastrointestinal stromal tumors: An independent adverse prognosticator associated with the non-gastric location

Yu Ching Wei, Chien Feng Li, Shih Chen Yu, Fong Fu Chou, Fu Min Fang, Hock Liew Eng, Yih Huei Uen, Yu Fang Tian, Jing Mei Wu, Shau Hsuan Li, Wen Wei Huang, Wei Ming Li, Hsuan Ying Huang

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Abstract

Ezrin, a member of the ezrin-radixin-moesin family, acts as a link between the cell membrane and actin cytoskeleton to integrate cell adhesion-mediated signaling. It implicates tumor progression, metastatic dissemination, and adverse outcomes in several cancer types, including pediatric and adult sarcomas. Although ezrin upregulation was shown by cDNA expression profiling, no study has systematically evaluated the significance of ezrin expression in a large cohort of gastrointestinal stromal tumors (GISTs). Ezrin immunostaining was carried out on tissue microarrays of primary GISTs and assessable in 347 cases, 188 of which were successfully evaluated for mutation variants of KIT and PDGFRA receptor tyrosine kinase (RTK) genes by sequencing with or without screening by denatured high-performance liquid chromatography. These GISTs with known RTK genotypes were dichotomized into two prognostically different groups. The endogenous expression and phosphorylation of ezrin in GIST cell lines were analyzed by western blotting. By immunohistochemistry, ezrin overexpression was present in 66% of GISTs and significantly associated with the non-gastric location (P0.002) and decreased disease-free survival (P0.032, univariately). However, it was not related to the National Institute of Health (NIH) risk category, Ki-67 labeling index, RTK genotypes, and other variables. In multivariate analyses, ezrin overexpression remained independently predictive of adverse outcome (P0.008, risk ratio2.363), together with Ki-67 labeling index 5% (P0.001, risk ratio3.581), high-risk category (P0.001, risk ratio2.156), and the non-gastric location (P0.029, risk ratio1.899). Despite the variation in the ezrin expression level, phosphorylated ezrin at threonine 567 was only detectable in GIST882 and GIST48 cells, but not in colonic smooth muscle cells. In conclusion, ezrin is frequently overexpressed in GISTs, especially those arising from the non-gastric sites. Given that its impact is independent of the NIH risk category, cell proliferation, and tumor location, ezrin immunoreactivity represents a valuable prognostic adjunct of GISTs, suggesting a causative role in conferring an aggressive phenotype.

Original languageEnglish
Pages (from-to)1351-1360
Number of pages10
JournalModern Pathology
Volume22
Issue number10
DOIs
Publication statusPublished - 2009 Oct 1

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine

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    Wei, Y. C., Li, C. F., Yu, S. C., Chou, F. F., Fang, F. M., Eng, H. L., Uen, Y. H., Tian, Y. F., Wu, J. M., Li, S. H., Huang, W. W., Li, W. M., & Huang, H. Y. (2009). Ezrin overexpression in gastrointestinal stromal tumors: An independent adverse prognosticator associated with the non-gastric location. Modern Pathology, 22(10), 1351-1360. https://doi.org/10.1038/modpathol.2009.107