title: NDRG2, suppressed expression associates with poor prognosis in pancreatic cancer, is hypermethylated in the second promoter in human gastrointestinal cancers.
abstract: Although N-myc downstream regulated gene 2 (NDRG2) is frequently downregulated in various cancers and is considered to be a candidate tumor suppressor gene, molecular mechanisms of the expressional suppression that lead to cancers are largely unknown. Recent studies indicated that epigenetic suppression of NDRG2 involved carcinogenesis and progression in several tumor types, and we demonstrated positive association with NDRG2 suppression and poor prognosis in pancreatic cancer. In this study, we analyzed mRNA and protein expressions of NDRG2 in 26 cancer cell lines (20 colorectal and 6 gastric cancers) and found that many cell lines showed variously reduced NDRG2 expressions. Furthermore, NDRG2 expressions were significantly reduced in primary resected cancer tissues compared to corresponding normal tissues immunohistochemically (19 of 20 colorectal and 14 of 17 gastric cancers). Treatment with 5-Aza-2' deoxycytidine predominantly upregulated NDRG2 expressions in NDRG2 low-expressing cell lines. Bisulfite sequencing analyses and methylation specific PCR revealed that methylation status at one of the two promoters (around exon 2) correlated well with the suppressed expression, and this is the major promoter in colorectal and gastric cancer cell lines. Our present results suggest that hypermethylation in promoter around exon 2 is functioning as essential factors of NDRG2 silencing in gastrointestinal cancers.
authors.affiliation: Department of Molecular Pathology, Tohoku University School of Medicine, Sendai, Japan; Department of Gastrointestinal Surgery, Tohoku University School of Medicine, Sendai, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Yamamura
authors.affiliation: Department of Gastrointestinal Surgery, Tohoku University School of Medicine, Sendai, Japan.
authors.forename: Koh
authors.initials: K
authors.lastname: Miura
authors.affiliation: Department of Gastrointestinal Surgery, Tohoku University School of Medicine, Sendai, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Karasawa
authors.affiliation: Department of Gastrointestinal Surgery, Tohoku University School of Medicine, Sendai, Japan.
authors.forename: Fuyuhiko
authors.initials: F
authors.lastname: Motoi
authors.affiliation: Department of Molecular Pathology, Tohoku University School of Medicine, Sendai, Japan.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Mizuguchi
authors.affiliation: Department of Molecular Pathology, Tohoku University School of Medicine, Sendai, Japan.
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Saiki
authors.affiliation: Department of Molecular Pathology, Tohoku University School of Medicine, Sendai, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Fukushige
authors.affiliation: Department of Molecular Pathology, Tohoku University School of Medicine, Sendai, Japan; Department of Gastrointestinal Surgery, Tohoku University School of Medicine, Sendai, Japan; Department of Digestive Tract Surgery and Transplantation Surgery, Tokyo Medical University Hachioji Medical Center, Tokyo, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Sunamura
authors.affiliation: Department of Gastrointestinal Surgery, Tohoku University School of Medicine, Sendai, Japan.
authors.forename: Chikashi
authors.initials: C
authors.lastname: Shibata
authors.affiliation: Department of Gastrointestinal Surgery, Tohoku University School of Medicine, Sendai, Japan.
authors.forename: Michiaki
authors.initials: M
authors.lastname: Unno
authors.affiliation: Department of Molecular Pathology, Tohoku University School of Medicine, Sendai, Japan. Electronic address: horii@med.tohoku.ac.jp.
authors.forename: Akira
authors.initials: A
authors.lastname: Horii
mesh_terms: D045744:Cell Line, Tumor; D018899:CpG Islands; D019175:DNA Methylation; D005770:Gastrointestinal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020868:Gene Silencing; D006801:Humans; D011379:Prognosis; D011401:Promoter Regions, Genetic; D012045:Regulatory Sequences, Nucleic Acid; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: C466228:NDRG2 protein, human; D025521:Tumor Suppressor Proteins
keywords: Gastrointestinal cancers; Hypermethylation; NDRG2; Type II transcript