Abstract
BackgroundThe epigenetic mechanism of tumorigenesis in pancreatic intraductal papillary mucinous neoplasm (IPMN) remains largely unknown. The aim of this study is to examine the role of enhancer of zeste homologue 2 (EZH2) alteration in pancreatic IPMN progression.MethodsFifty-four surgically resected pancreatic IPMN specimens, including a total of 181 lesions (normal duct in 48, adenoma in 50, borderline atypia in 53, carcinoma in situ (CIS) in 19, and invasive carcinoma in 11) were analyzed by immunohistochemical staining (EZH2, Ki-67, p27Kip1). Using paraffin embedded sections, total RNA was successfully extracted from 20 IPMN lesions (borderline IPMN in 9, CIS in 6, invasive carcinoma in 5) and 7 pancreatic normal ducts, and then levels of EZH2 and p27Kip1 mRNA were analyzed by real time PCR.ResultsIn immunohistochemical analysis, cell proliferative activity revealed by Ki-67 positive nuclei was increased during IPMN progression (normal duct<adenoma<borderline atypia<CIS ≈ invasive carcinoma). EZH2 expression displayed a similar pattern (normal duct<adenoma<borderline atypia<CIS ≈ invasive carcinoma) with cell proliferative activity. EZH2 expression in malignant (CIS and invasive carcinoma) IPMNs was significantly higher than that in adenoma and borderline-atypia IPMNs. EZH2 expression level in IPMN lesions was positively correlated with the Ki-67 positive nuclear ratio (p<0.0001). EZH2-positive cells in malignant IPMN did not express p27Kip1. EZH2 mRNA expressions in malignant lesions were significantly higher than those in benign lesions (p<0.0001). In contrast, p27Kip1 mRNA in malignant lesions was significantly decreased compared to those in benign lesion (p<0.05), and there was an inverse correlation between EZH2 and p27Kip1 mRNA levels (p = 0.0109).ConclusionEZH2 is associated with the accelerated cell proliferation and malignant step in pancreatic IPMN via the downregulation of p27Kip1.
Highlights
Cystic pancreatic lesions have been shown in up to 25% of in autopsy cases; 5% of these lesions are neoplastic, such as intraductal papillary mucious neoplasms (IPMNs) and mucinous cystic neoplasms [1,2]
We report that enhancer of zeste homologue 2 (EZH2) is associated with the accelerated cell proliferation and malignant step in pancreatic IPMN via the gene silencing of p27Kip1
Our series of 54 resected specimens included a total of 181 lesions (48 normal duct and 133 IPMN lesions), including 50 with adenoma, 53 with borderline atypia, 19 with carcinoma in site (CIS), and 11 with invasive carcinoma
Summary
Cystic pancreatic lesions have been shown in up to 25% of in autopsy cases; 5% of these lesions are neoplastic, such as intraductal papillary mucious neoplasms (IPMNs) and mucinous cystic neoplasms [1,2]. Its molecular mechanism of oncogenesis remains largely unknown due to the limited research tools, such as the availability of only resected human specimens. Oncogenesis is a complex process associated with the accumulation of genetic and epigenetic defects that alter the transcriptional program. The epigenetic mechanism of tumorigenesis in pancreatic IPMN remains largely unknown. The. The epigenetic mechanism of tumorigenesis in pancreatic intraductal papillary mucinous neoplasm (IPMN) remains largely unknown. The aim of this study is to examine the role of enhancer of zeste homologue 2 (EZH2) alteration in pancreatic IPMN progression
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