title: Epigenetic suppression of the immunoregulator MZB1 is associated with the malignant phenotype of gastric cancer.
abstract: Prediction of tumor recurrence after curative resection is critical for determining the prognosis of patients with gastric cancer (GC). The initiation and progression of GC are associated with inappropriate immune responses caused by chronic inflammation of the gastric mucosa. To identify immunoregulatory molecules involved in GC progression, GC cell lines and 200 pairs of tumor and normal tissues from patients with GC were analyzed for gene expression, amplification and methylation as well as function of a differentially expressed gene. The transcriptome analysis revealed that marginal zone B and B1 cell specific protein (MZB1) was expressed at significantly decreased levels in primary GC tissues when compared with the corresponding normal gastric mucosa. PCR array analysis exploring genes expressed cooperatively with MZB1 revealed that differential expression of MZB1 mRNA in GC cell lines correlated positively with the levels of the mRNAs encoding estrogen receptor 1 and desumoylating isopeptidase 1. Hypermethylation of the MZB1 promoter was frequent in cell lines with decreased levels of MZB1 mRNA. siRNA-mediated knockdown of MZB1 significantly increased proliferation, invasion and migration of GC cell lines. Low MZB1 expression was an independent prognostic factor for recurrence after curative gastrectomy and was associated significantly with increased hematogenous recurrence. MZB1 acts as a suppressor of GC. Low MZB1 expression in the primary GC tissue is predictive of recurrence after curative resection.
authors.affiliation: Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan. m-kanda@med.nagoya-u.ac.jp.
authors.forename: Mitsuro
authors.initials: M
authors.lastname: Kanda
authors.affiliation: Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Chie
authors.initials: C
authors.lastname: Tanaka
authors.affiliation: Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kobayashi
authors.affiliation: Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Haruyoshi
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Dai
authors.initials: D
authors.lastname: Shimizu
authors.affiliation: Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Shibata
authors.affiliation: Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Takami
authors.affiliation: Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Masamichi
authors.initials: M
authors.lastname: Hayashi
authors.affiliation: Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Iwata
authors.affiliation: Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Niwa
authors.affiliation: Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Suguru
authors.initials: S
authors.lastname: Yamada
authors.affiliation: Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Fujii
authors.affiliation: Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Goro
authors.initials: G
authors.lastname: Nakayama
authors.affiliation: Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Michitaka
authors.initials: M
authors.lastname: Fujiwara
authors.affiliation: Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kodera
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D009367:Neoplasm Staging; D010641:Phenotype; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D013274:Stomach Neoplasms / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; C434482:MZB1 protein, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering
keywords: biomarker; gastric cancer; marginal zone B and B1 cell specific protein; methylation; recurrence