title: The relationship between EZH2 expression and microRNA-31 in colorectal cancer and the role in evolution of the serrated pathway.
abstract: Polycomb group protein enhancer of zeste homolog 2 (EZH2) is a methyltransferase that correlates with the regulation of invasion and metastasis and is overexpressed in human cancers such as colorectal cancer. MicroRNA-31 (miR-31) plays an oncogenic role and is associated with BRAF mutation and poor prognosis in colorectal cancer. EZH2 is functionally considered to suppress miR-31 expression in human cancers; however, no study has reported its relationship with colon cancer. We therefore evaluated EZH2 expression using immunohistochemistry and assessed miR-31 and epigenetic alterations using 301 colorectal carcinomas and 207 premalignant lesions. Functional analysis was performed to identify the association between EZH2 and miR-31 using cancer cell lines. In the current study, negative, weak, moderate, and strong EZH2 expressions were observed in 15%, 19%, 25%, and 41% of colorectal cancers, respectively. EZH2 was inversely associated with miR-31 (P < 0.0001), independent of clinicopathological and molecular features. In a multivariate stage-stratified analysis, high EZH2 expression was related to favorable prognosis (P = 0.0022). Regarding premalignant lesions, negative EZH2 expression was frequently detected in sessile serrated adenomas/polyps (SSA/Ps) (76%; P < 0.0001) compared with hyperplastic polyps, traditional serrated adenomas, and non-serrated adenomas (25-36%). Functional analysis demonstrated that the knockdown of EZH2 increased miR-31 expression. In conclusion, an inverse association was identified between EZH2 and miR-31 in colorectal cancers. Our data also showed that upregulation of EZH2 expression may be rare in SSA/Ps. These results suggest that EZH2 suppresses miR-31 in colorectal cancer and may correlate with differentiation and evolution of serrated pathway.
authors.affiliation: Department of Gastroenterology, Rheumatology and Clinical Immunology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Kurihara
authors.affiliation: Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Reo
authors.initials: R
authors.lastname: Maruyama
authors.affiliation: Department of Gastroenterology, Rheumatology and Clinical Immunology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Ishiguro
authors.affiliation: Department of Gastroenterology, Rheumatology and Clinical Immunology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kanno
authors.affiliation: Department of Gastroenterology, Rheumatology and Clinical Immunology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Itaru
authors.initials: I
authors.lastname: Yamamoto
authors.affiliation: Department of Gastroenterology, Rheumatology and Clinical Immunology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Ishigami
authors.affiliation: Department of Gastroenterology, Rheumatology and Clinical Immunology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Mitsuhashi
authors.affiliation: Department of Gastroenterology, Rheumatology and Clinical Immunology, Sapporo Medical University School of Medicine, Sapporo, Japan.|The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Hisayoshi
authors.initials: H
authors.lastname: Igarashi
authors.affiliation: Department of Gastroenterology, Rheumatology and Clinical Immunology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Ito
authors.affiliation: Department of Gastroenterology, Rheumatology and Clinical Immunology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Tokuma
authors.initials: T
authors.lastname: Tanuma
authors.affiliation: Department of Gastroenterology, Rheumatology and Clinical Immunology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Sukawa
authors.affiliation: Department of Surgery, Surgical Oncology and Science, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Okita
authors.affiliation: Department of Surgical Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Hasegawa
authors.affiliation: The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Kohzoh
authors.initials: K
authors.lastname: Imai
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yamamoto
authors.affiliation: Department of Gastroenterology, Ikeda Municipal Hospital, Ikeda, Japan.
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Shinomura
authors.affiliation: Department of Gastroenterology, Rheumatology and Clinical Immunology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Nosho
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018256:Adenomatous Polyps / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D003111:Colonic Polyps / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D011230:Precancerous Conditions / Q000235:genetics / Q000378:metabolism / Q000473:pathology*
chemical_list: C534612:MIRN31 microRNA, human; D035683:MicroRNAs; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein
keywords: CIMP; ChIP; EGFR; EZH2; H3K27me3