Differentially expressed gene analysis associated with malignant progression of intraductal papillary mucinous neoplasm and prognostic significance of E-cadherin and ZEB1 expression

Abstract

There is an urgent need to investigate the genetic changes that occur in intraductal papillary mucinous neoplasm (IPMN), which is a well-known precursor of pancreatic cancer. In this study, gene expression profiling was performed to determine the differentially expressed genes (DEGs) associated with malignant progression of IPMN. To overcome a histologic heterogeneity of IPMN, Removing Unwanted Variation method was performed for normalization and determination of DEGs. Among the identified DEGs using 18 fresh-frozen tissues, zinc finger E-box binding homeobox 1 (ZEB1) and E-cadherin, a crucial regulator of epithelial-to-mesenchymal transition (EMT), was validated. <br/> Formalin-fixed, paraffin-embedded blocks from 87 patients were obtained for immunohistochemical analysis. Loss of E- cadherin expression (p = 0.023, odd ratio [OR] = 4.923) and expression of ZEB1 in stromal cells (stromal ZEB1, p < 0.001, OR = 26.800) were significantly correlated with degree of dysplasia. The hazard of death was significantly increased in patients with loss of E-cadherin expression (hazard ratio [HR] = 13.718, p = 0.004), expression of epithelial ZEB1 (HR = 19.117, p = 0.001), and stromal ZEB1 (HR = 6.373, p = 0.043). <br/> Based on the results of this study, loss of E-cadherin and expression of stromal ZEB1 are associated with increased risk of malignant progression. Epithelial and stromal ZEB1, as well as E-cadherin may be strong predictors of survival in patients with IPMN. Our finding suggests that these EMT markers may be utilized as potential prognosticators and may be used to improve and personalize treatment of IPMN.<br/>