title: Loss of runt-related transcription factor 3 induces gemcitabine resistance in pancreatic cancer.
abstract: OBJECTIVE
  Runt-related transcription factor 3 (RUNX3) is a tumor suppressor gene that is expressed in gastric and other cancers including pancreatic cancer. However, the precise function of RUNX3 in pancreatic cancer has not been fully elucidated. In this study, we aimed to determine the effect of decreased RUNX3 expression in pancreatic cancer.
  
  
  METHODS
  This study included 36 patients with primary pancreatic cancer, who had undergone pancreaticoduodenectomy. All patients were treated with 1000 mg/m2 gemcitabine after the surgery. The pancreatic cancer cell lines PANC-1, MIAPaCa-2, BxPC-3, SUIT-2, and KLM-1 were used for immunoblotting analysis of RUNX3 and multidrug resistance protein (MRP) expressions. Ectopic RUNX3 expression was achieved by cDNA transfection of the cells, and small interfering RNA (siRNA) against RUNX3 was used to knock down endogenous RUNX3. Cell growth in the presence of gemcitabine was assessed using the MTT assay.
  
  
  RESULTS
  Patients with RUNX3-positive and RUNX3-negative pancreatic cancer had a median survival of 1006 and 643 days, respectively. Exogenous RUNX3 expression reduced the expression of MRP1, MRP2, and MRP5 in endogenous RUNX3-negative cells, whereas RUNX3 siRNA increased the expressions of these genes in endogenous RUNX3-positive cells. Exogenous RUNX3 expression decreased gemcitabine IC50 in RUNX3-negative cells.
  
  
  CONCLUSIONS
  Loss of RUNX3 expression contributes to gemcitabine resistance by inducing MRP expression, thereby resulting in poor patient survival.
authors.affiliation: Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Kita-ku, Okayama, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Horiguchi
authors.forename: Hidenori
authors.initials: H
authors.lastname: Shiraha
authors.forename: Teruya
authors.initials: T
authors.lastname: Nagahara
authors.forename: Jyunnro
authors.initials: J
authors.lastname: Kataoka
authors.forename: Masaya
authors.initials: M
authors.lastname: Iwamuro
authors.forename: Minoru
authors.initials: M
authors.lastname: Matsubara
authors.forename: Shinichi
authors.initials: S
authors.lastname: Nishina
authors.forename: Hironari
authors.initials: H
authors.lastname: Kato
authors.forename: Akinobu
authors.initials: A
authors.lastname: Takaki
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nouso
authors.forename: Takehiro
authors.initials: T
authors.lastname: Tanaka
authors.forename: Koichi
authors.initials: K
authors.lastname: Ichimura
authors.forename: Takahito
authors.initials: T
authors.lastname: Yagi
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Yamamoto
mesh_terms: D045744:Cell Line, Tumor; D050677:Core Binding Factor Alpha 3 Subunit / Q000235:genetics / Q000378:metabolism*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D006801:Humans; D015151:Immunoblotting; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000601:surgery; D016577:Pancreaticoduodenectomy; D034741:RNA, Small Interfering; D000093542:Gemcitabine
chemical_list: D050677:Core Binding Factor Alpha 3 Subunit; D034741:RNA, Small Interfering; D003841:Deoxycytidine; D000093542:Gemcitabine
keywords: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; 5-FU; 5-fluorouracil; ABC; ABCC; ATP-binding cassette; ATP-binding cassette subfamily C; Adjuvant chemotherapy; CAT; FBS; MRP; MTT; Pancreaticoduodenectomy; RUNX3; Runt-related transcription factor 3 (RUNX3); SDS; Survival; TBS-T; TGF-β; Tris-buffered saline with Tween 20; cDNA; chloramphenicol acetyltransferase; complementary DNA; fetal bovine serum; multidrug resistance protein; runt-related transcriptional factor 3; siRNA; small interfering RNA; sodium dodecyl sulfate; transforming growth factor-β