Abstract
Abstract BACKGROUND: Intraductal papillary mucinous neoplasms (IPMNs) include various degree of dysplasia, and are supposed to be one of the precursors of pancreatic ductal adenocarcinoma (PDCA), however, IPMN carcinogenesis has not yet been established. MicroRNAs (miRNA) may be directly implicated in some carcinogenic process. These miRNAs can function as tumor suppressors or oncogenes. Enhancer of zeste homolog 2 (EZH2) contributes to the epigenetic silencing of target genes, and plays a pivotal role in the etiology of tumorigenisity in several cancers. PURPOSE: This study aimed to (1) evaluate whether expression of EZH2 promotes neoplastic progression of IPMN and PDCA, and (2) elucidate regulation of EZH2 expression by miR-101. METHODS: EZH2 mRNA and protein expression was investigated in eight human pancreatic cancer cell lines (PANC-1, PK8, PK9, PK-59, KLM-1, MIA PaCa2, Hs-700T, PK-45P) by PCR and western blotting. Pre-miR-101, and anti-miR-101 was transfected into pancreatic cancer cells to elucidate regulation of EZH2 by miR-101. To evaluate whether EZH2 modulates malignant progression of IPMN, EZH2 expression in both benign and malignant IPMN was examined in 54 patients by immunohistochemistry. Next, we collected malignant and benign cells from formalin-fixed paraffin-embedded samples of IPMNs using laser capture microdissection, and extracted RNA. MiR-101 expression in IPMN was assessed using real-time PCR. RESULTS: All pancreatic cancer cell lines expressed EZH2 mRNA and protein. The induction of miR-101 by transfection of pre-miR-101 in MIA PaCa-2 was closely related to a reduction in EZH2 protein production compared with control, whereas there was little difference in the expression of EZH2 mRNA. Anti-miR-101 transfected pancreatic cancer cells showed increase in EZH2 protein, while EZH2 mRNA level was not elevated. Immunohistochemistry revealed that the expression of EZH2 was significantly higher in malignant than benign IPMN. Expression of MiR-101 was significantly lower in malignant than benign IPMN. CONCLUSIONS: MiR-101 targets EZH2 at the posttranscriptional level, and loss of miR-101 could be a trigger for the adenoma-carcinoma sequence of IPMN by up-regulation of EZH2. This study suggests miR-101- EZH2 blockade as a potential therapeutic target in IPMN carcinogenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3971. doi:10.1158/1538-7445.AM2011-3971
Published Version
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