title: Expression of ribonucleotide reductase M2 subunit in gastric cancer and effects of RRM2 inhibition in vitro.
abstract: Ribonucleotide reductase M2 subunit is one of two subunits that constitute ribonucleotide reductase, the enzyme that catalyzes the conversion of ribonucleotide 5'-diphosphates into 2'-deoxyribonucleotides, which are required for DNA synthesis. This study was conducted to investigate the roles of ribonucleotide reductase M2 subunit in gastric cancer. The expression of ribonucleotide reductase M2 subunit protein was examined by immunohistochemistry. In normal gastric mucosa, ribonucleotide reductase M2 subunit expression was restricted to the neck regions of gastric pits and no expression was observed in the surface epithelium. Among 112 gastric cancer tissues, ribonucleotide reductase M2 subunit overexpression (≥10% cancer cells stained) was observed in 72 cases (64.3%). Ribonucleotide reductase M2 subunit overexpression was significantly associated with male sex (P = .015), presence of muscularis propria invasion (P = .020), presence of Epstein-Barr virus (P = .045), expression of survivin (P = .0014), and DNA methyltransferase 1 (P = .043), but not with age, histology, tumor size, lymph node metastasis or expression of phosphatase and tensin homolog, phosphorylated signal transducer, and activator of transcription 3 or p53. Suppression of ribonucleotide reductase M2 subunit synthesis, using small interfering RNA, inhibited the growth of 3 gastric cancer cell lines, MKN-1, MKN-7, and SNU-719. Our data suggest that ribonucleotide reductase M2 subunit overexpression could be associated with the gastric cancer progression and that suppression of its function is a potential therapeutic strategy in gastric cancer.
authors.affiliation: Department of Pathology, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan.
authors.forename: Teppei
authors.initials: T
authors.lastname: Morikawa
authors.forename: Rumi
authors.initials: R
authors.lastname: Hino
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Uozaki
authors.forename: Daichi
authors.initials: D
authors.lastname: Maeda
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Ushiku
authors.forename: Aya
authors.initials: A
authors.lastname: Shinozaki
authors.forename: Takashi
authors.initials: T
authors.lastname: Sakatani
authors.forename: Masashi
authors.initials: M
authors.lastname: Fukayama
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology* / Q000473:pathology / Q000821:virology; D045744:Cell Line, Tumor; D002470:Cell Survival; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D020031:Epstein-Barr Virus Infections; D005260:Female; D005753:Gastric Mucosa; D020868:Gene Silencing; D004854:Herpesvirus 4, Human / Q000302:isolation & purification; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008198:Lymph Nodes / Q000473:pathology; D008207:Lymphatic Metastasis; D008297:Male; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D034741:RNA, Small Interfering / Q000235:genetics; D012262:Ribonucleoside Diphosphate Reductase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000201:enzymology* / Q000473:pathology / Q000821:virology; D046888:Tissue Array Analysis; D014162:Transfection
chemical_list: D004791:Enzyme Inhibitors; D034741:RNA, Small Interfering; C093713:ribonucleotide reductase M2; D012262:Ribonucleoside Diphosphate Reductase