Abstract 5353: EZH2-mediated, but not BMI-1, epigenetic alteration may be associated with the accelerated cell proliferation and malignant step in IPMN.
Authors: Kuroki Hideyuki 
Published: August 2014

Backgrounds. Histologic examination of IPMNs shows the co-existence of benign and malignant lesions within a single specimen of the pancreas represented by multifocality. Thus, IPMNs of pancreas are characterized by multifocal and malignant potential represented by an adenomacarcinoma sequence, whereas its molecular mechanism of oncogenesis remains largely unknown. Recently, epigenetic gene silencing in cancer is now increasingly recognized as a novel therapeutic target. The histone methyltransferase Enhancer of Zeste 2 (EZH2) is associated with transcriptional repression. B-lymphoma moloney murine leukemia virus insertion-1 (BMI-1). is a proto-oncogene that belongs to polycom group gene family. The role of epigenetic alteration mediated by EZH2 and BMI-1 in IPMNs progression is unclear.

Method. From 2002 to 2011, 54 patients with IPMN underwent curative pancreatic resection. The total 133 IPMN lesions and 48 normal duct epithelial lesions within IPMN lesion were analyzed in this study. In the present study, a total of 133 IPMN lesions were classified as either benign (adenoma and borderline tumors)or malignant (carcinoma in situ or invasive cancer). Result. Fifty-four cases of IPMNs consists of 23 IPMC (91 lesions) and 31 IPMA (90 lesions). We assessed to a proliferative activity in IPMNs by Ki-67 immunostainig. The number of Ki-67 positive cell was significantly increased during the progression of IPMNs. In malignant IPMN, Ki-67 positive cell was significantly increased compared with that in benign IPMN. Thus, the increased proliferative activity plays an important role in an adenoma-carcinoma sequence of IPMNs. The expression of cell-cycle related suppressor protein, p27Kip1 expression was inversely down-regulated during the progression of IPMNs. To further assess the molecular mechanism of the downregulated p27KIP1 expression during the progression of IPMNs, we focused the epigenetic epigenetic gene silencing during the tumor progression. The EZH2 expression was increased step by step during the progression of the IPMNs. In benign IPMN (IPMA), EZH2-negative cells expressed p27KIP1 protein. In contrast, in malignant IPMN (CIS lesion), EZH2-positive cells unexpressed p27KIP1 protein, suggesting that the increased EZH2 expression during the progression of IPMNs suppress the p27KIP1 protein expression. Furthermore, EZH2 expression level in IPMNs showed the significantly positive correlation with the Ki-67 positive nuclear ratio (p&lt;0.0001). However, there was no significant association between BMI-1 expression and Ki-67 positive nuclear ratio.

Conclusion. Here, we show EZH2-mediated, but not BMI-1, epigenetic alteration as a novel oncogenetic mechanism in IPMNs. EZH2-mediated epigenetic alteration may be associated with the accelerated cell proliferation and malignant step in IPMN via a downregulation of p27KIP1.

Citation Format: Hideyuki Kuroki. EZH2-mediated, but not BMI-1, epigenetic alteration may be associated with the accelerated cell proliferation and malignant step in IPMN. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5353. doi:10.1158/1538-7445.AM2013-5353