title: Nuclear PRMT1 expression is associated with poor prognosis and chemosensitivity in gastric cancer patients.
abstract: BACKGROUND
  Metastatic and refractory gastric cancer (GC) are associated with a poor prognosis; therefore, the identification of prognostic factors and chemosensitivity markers is extremely important. Protein arginine methyltransferase 1 (PRMT1) may play a role in chemosensitivity/apoptosis induction via activation of the tumor suppressor forkhead box O1 (FOXO1). The purpose of this study was to clarify the expression of and relationship between PRMT1 and FOXO1 to evaluate the applicability of PRMT1 as a prognostic marker and a therapeutic tool in GC.
  
  
  METHODS
  We investigated the clinical and functional significance of PRMT1 and FOXO1 in 195 clinical GC samples using immunohistochemistry. We performed suppression analysis of PRMT1 using small interfering RNA to determine the biological roles of PRMT1 in chemosensitivity.
  
  
  RESULTS
  PRMT1 and FOXO1 in GC samples were predominantly expressed in the nucleus. Patients with lower PRMT1 expression (n = 131) had suppressed nuclear accumulation of FOXO1, higher recurrence after adjuvant chemotherapy, and poorer prognosis than those with higher PRMT1 expression (n = 64). PRMT1 downregulation in GC cells by RNA interference inhibited cisplatin and 5-fluorouracil sensitivity. The expression of phosphorylated FOXO1 and phosphorylated BCL-2 antagonist of cell death was upregulated in PRMT1 small interfering RNA groups.
  
  
  CONCLUSIONS
  Our data suggest that the evaluation of PRMT1 expression in GC is a useful predictor of poor prognosis and recurrence after adjuvant chemotherapy. Moreover, these data suggest that PRMT1 is a promising therapeutic tool for overcoming refractory GC.
authors.affiliation: Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma, Japan.
authors.forename: Bolag
authors.initials: B
authors.lastname: Altan
authors.affiliation: Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma, Japan. bori45@gunma-u.ac.jp.
authors.forename: Takehiko
authors.initials: T
authors.lastname: Yokobori
authors.affiliation: Department of Diagnostic Pathology, Graduate School of Medicine, Gunma University, Maebashi, Gunma, Japan.
authors.forename: Munenori
authors.initials: M
authors.lastname: Ide
authors.affiliation: Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Saitama, Japan.
authors.forename: Erito
authors.initials: E
authors.lastname: Mochiki
authors.affiliation: Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Toyomasu
authors.affiliation: Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma, Japan.
authors.forename: Norimichi
authors.initials: N
authors.lastname: Kogure
authors.affiliation: Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma, Japan.
authors.forename: Akiharu
authors.initials: A
authors.lastname: Kimura
authors.affiliation: Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma, Japan.
authors.forename: Keigo
authors.initials: K
authors.lastname: Hara
authors.affiliation: Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma, Japan.
authors.forename: Tuya
authors.initials: T
authors.lastname: Bai
authors.affiliation: Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma, Japan.
authors.forename: Pinjie
authors.initials: P
authors.lastname: Bao
authors.affiliation: Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma, Japan.
authors.forename: Kyoichi
authors.initials: K
authors.lastname: Ogata
authors.affiliation: Department of Oncology Clinical Development, Graduate School of Medicine, Gunma University, Maebashi, Gunma, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Asao
authors.affiliation: Department of Molecular Pharmacology and Oncology, Graduate School of Medicine, Gunma University, Maebashi, Gunma, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Nishiyama
authors.affiliation: Department of Diagnostic Pathology, Graduate School of Medicine, Gunma University, Maebashi, Gunma, Japan.
authors.forename: Tetsunari
authors.initials: T
authors.lastname: Oyama
authors.affiliation: Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kuwano
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000556:secondary*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015153:Blotting, Western; D018279:Carcinoma, Signet Ring Cell / Q000188:drug therapy / Q000378:metabolism / Q000556:secondary*; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use*; D005500:Follow-Up Studies; D000071161:Forkhead Box Protein O1 / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D017404:In Situ Hybridization, Fluorescence; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011379:Prognosis; D011484:Protein-Arginine N-Methyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D015996:Survival Rate; D014407:Tumor Cells, Cultured
chemical_list: D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D034741:RNA, Small Interfering; D012097:Repressor Proteins; C099988:PRMT1 protein, human; D011484:Protein-Arginine N-Methyltransferases; D005472:Fluorouracil
keywords: Arginine methyltransferase; Forkhead box O1; Noncoding RNA; Protein arginine methyltransferases