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 by removing unwanted variation to determine the differentially expressed genes (DEGs) associated with malignant progression of IPMN. Among the identified DEGs, zinc finger E-box binding homeobox 1 (ZEB1) and E-cadherin, a crucial regulator of epithelial-to-mesenchymal transition (EMT), was validated among identified DEGs.A total of 76 fresh-frozen tissues were used for gene expression profiling and 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).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.
Highlights
Intraductal papillary mucinous neoplasm (IPMN) has been increasingly recognized as an important cystic precursor of pancreatic cancer [1]
One transcription factor that orchestrates the epithelialto-mesenchymal transition (EMT) is zinc finger E-box binding homeobox 1 (ZEB1), which is encoded by the TCF8 gene, and is the vertebrate homologue of the ZFH gene family of zinc finger/homeodomain proteins
Gene expression changes associated with EMT during the progression of intraductal papillary mucinous neoplasm (IPMN) was first examined in a study by gene set enrichment analysis (GSEA) and Ariadne sub-network analysis in 28 IPMN samples [10]
Summary
Intraductal papillary mucinous neoplasm (IPMN) has been increasingly recognized as an important cystic precursor of pancreatic cancer [1]. It has been suggested that IPMN undergoes a progression pattern, which consists of hyperplasia, dysplasia, and invasive carcinoma sequence [2, 3]. Numerous efforts have been made to identify the genetic changes associated with progression of IPMN. Since preoperative assessment of gene expression profiling has been used to differentiate invasive from noninvasive IPMNs [4], GNAS and KRAS mutations have been identified by direct sequencing [5], and immunohistochemical analysis suggested correlations between fascin overexpression and increased histological grade of IPMN [6]. Loss of expression of PTEN [8] and Plectin-1 [9] have been reported to be associated with poor prognosis or malignant progression of IPMN
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