title: EZH2 is associated with malignant behavior in pancreatic IPMN via p27Kip1 downregulation.
abstract: BACKGROUND
  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.
  
  
  METHODS
  Fifty-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.
  
  
  RESULTS
  In 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).
  
  
  CONCLUSIONS
  EZH2 is associated with the accelerated cell proliferation and malignant step in pancreatic IPMN via the downregulation of p27Kip1.
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Kuroki
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Hayashi
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Okabe
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Hashimoto
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takamori
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Nakahara
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Nakagawa
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Fukushima
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Chikamoto
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Beppu
authors.affiliation: Department of Surgery, Kumamoto Regional Medical Center, Kumamoto, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Hirota
authors.affiliation: Department of Surgical Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Iyama
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Baba
mesh_terms: D002288:Adenocarcinoma, Mucinous / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000368:Aged; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002291:Carcinoma, Papillary / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D015536:Down-Regulation; D000071221:Enhancer of Zeste Homolog 2 Protein; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D063150:Polycomb Repressive Complex 1 / Q000235:genetics / Q000378:metabolism; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism*
chemical_list: C069077:BMI1 protein, human; D050760:Cyclin-Dependent Kinase Inhibitor p27; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D063150:Polycomb Repressive Complex 1
references.citation: Radiology. 2002 May;223(2):547-53
references.pmid: 11997566
references.citation: Int J Pancreatol. 1995 Dec;18(3):197-206
references.pmid: 8708390
references.citation: Oncol Rep. 2003 Jan-Feb;10(1):21-5
references.pmid: 12469138
references.citation: Clin Cancer Res. 2012 Aug 1;18(15):4201-12
references.pmid: 22675170
references.citation: Nature. 2002 Oct 10;419(6907):624-9
references.pmid: 12374981
references.citation: Mol Cancer Ther. 2009 Jun;8(6):1579-88
references.pmid: 19509260
references.citation: Ann Surg. 2001 Sep;234(3):313-21; discussion 321-2
references.pmid: 11524584
references.citation: Int J Cancer. 2012 Jun 1;130(11):2557-67
references.pmid: 21717453
references.citation: J Gastrointest Surg. 2011 Mar;15(3):503-11
references.pmid: 21225475
references.citation: Clin Cancer Res. 2007 Aug 1;13(15 Pt 1):4371-7
references.pmid: 17671118
references.citation: Cancer. 2001 Oct 1;92(7):1807-17
references.pmid: 11745253
references.citation: Am J Gastroenterol. 2002 Oct;97(10):2553-8
references.pmid: 12385438
references.citation: Ann Surg. 2004 Jun;239(6):788-97; discussion 797-9
references.pmid: 15166958
references.citation: Ann Surg. 2004 May;239(5):678-85; discussion 685-7
references.pmid: 15082972
references.citation: Virchows Arch. 2002 Nov;441(5):437-43
references.pmid: 12447672
references.citation: Hepatogastroenterology. 2000 Jul-Aug;47(34):1129-34
references.pmid: 11020896
references.citation: Cancer Sci. 2010 Jul;101(7):1754-60
references.pmid: 20426791
references.citation: Clin Cancer Res. 2008 Nov 1;14(21):6790-6
references.pmid: 18980972
references.citation: Oncologist. 2009 Feb;14(2):125-36
references.pmid: 19211618
references.citation: Proc Natl Acad Sci U S A. 2003 Sep 30;100(20):11606-11
references.pmid: 14500907
references.citation: Genes Dev. 2012 Mar 1;26(5):439-44
references.pmid: 22391448
references.citation: Ann Surg. 1997 Oct;226(4):491-8; discussion 498-500
references.pmid: 9351717
references.citation: Science. 2002 Nov 1;298(5595):1039-43
references.pmid: 12351676
references.citation: Pancreas. 1996 May;12(4):362-8
references.pmid: 8740403
references.citation: Mol Cancer Res. 2011 Apr;9(4):418-29
references.pmid: 21383005
references.citation: Breast Cancer Res. 2009;11(4):R63
references.pmid: 19709408
references.citation: Gut. 2002 Jun;50(6):861-8
references.pmid: 12010891
references.citation: Lung Cancer. 2012 Nov;78(2):138-43
references.pmid: 22925699
references.citation: J Cell Biochem. 2011 Jul;112(7):1938-48
references.pmid: 21445878