title: Suppressed expression of NDRG2 correlates with poor prognosis in pancreatic cancer.
abstract: Pancreatic cancer is a highly lethal disease with a poor prognosis; the molecular mechanisms of the development of this disease have not yet been fully elucidated. N-myc downstream regulated gene 2 (NDRG2), one of the candidate tumor suppressor genes, is frequently downregulated in pancreatic cancer, but there has been little information regarding its expression in surgically resected pancreatic cancer specimens. We investigated an association between NDRG2 expression and prognosis in 69 primary resected pancreatic cancer specimens by immunohistochemistry and observed a significant association between poor prognosis and NDRG2-negative staining (P=0.038). Treatment with trichostatin A, a histone deacetylase inhibitor, predominantly up-regulated NDRG2 expression in the NDRG2 low-expressing cell lines (PANC-1, PCI-35, PK-45P, and AsPC-1). In contrast, no increased NDRG2 expression was observed after treatment with 5-aza-2' deoxycytidine, a DNA demethylating agent, and no hypermethylation was detected in either pancreatic cancer cell lines or surgically resected specimens by methylation specific PCR. Our present results suggest that (1) NDRG2 is functioning as one of the candidate tumor-suppressor genes in pancreatic carcinogenesis, (2) epigenetic mechanisms such as histone modifications play an essential role in NDRG2 silencing, and (3) the expression of NDRG2 is an independent prognostic factor in pancreatic cancer.
authors.affiliation: Department of Surgery, Tohoku University, Graduate School of Medicine, Sendai, Japan; Department of Pathology, Tohoku University, Graduate School of Medicine, Sendai, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Yamamura
authors.forename: Koh
authors.initials: K
authors.lastname: Miura
authors.forename: Hideaki
authors.initials: H
authors.lastname: Karasawa
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Morishita
authors.forename: Keiko
authors.initials: K
authors.lastname: Abe
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Mizuguchi
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Saiki
authors.forename: Shinichi
authors.initials: S
authors.lastname: Fukushige
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kaneko
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Sase
authors.forename: Hiroki
authors.initials: H
authors.lastname: Nagase
authors.forename: Makoto
authors.initials: M
authors.lastname: Sunamura
authors.forename: Fuyuhiko
authors.initials: F
authors.lastname: Motoi
authors.forename: Shinichi
authors.initials: S
authors.lastname: Egawa
authors.forename: Chikashi
authors.initials: C
authors.lastname: Shibata
authors.forename: Michiaki
authors.initials: M
authors.lastname: Unno
authors.forename: Iwao
authors.initials: I
authors.lastname: Sasaki
authors.forename: Akira
authors.initials: A
authors.lastname: Horii
mesh_terms: D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics; D000077209:Decitabine; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology / Q000627:therapeutic use; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D016624:Negative Staining; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D011379:Prognosis; D011401:Promoter Regions, Genetic; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D006877:Hydroxamic Acids; C466228:NDRG2 protein, human; D025521:Tumor Suppressor Proteins; C012589:trichostatin A; D000077209:Decitabine; D001374:Azacitidine
keywords: 5-aza-2′ deoxycytidine; 5-aza-dC; AU; B2M; Epigenetic silencing; HDAC; Hypermethylation; MSP; N-myc downstream regulated gene 2; NDRG2; Pancreatic cancer; Prognostic factor; TSA; arbitrary unit; cDNA; complementary DNA; histone deacetylase; methylation-specific PCR; qRT-PCR; quantitative reverse transcription polymerase chain reaction; trichostatin A; β2-microglobulin