title: Cancer Stem-like Properties in Colorectal Cancer Cells with Low Proteasome Activity.
abstract: OBJECTIVE
  One of the main reasons for cancer treatment resistance is the existence of cancer stem-like cells (CSCs). Here, we elucidated the relationship between low proteasome activity cells (LPACs) and CSCs.
  
  
  METHODS
  The human colorectal cancer cell lines HCT116, SW480, DLD1, and KM12SM were engineered to stably express a green fluorescent molecule fused to the degron of ornithine decarboxylase, resulting in an accumulation of the fluorescence in LPACs. LPACs were isolated by flow cytometry. Treatment resistance (radio- and chemotherapy) and the capacity of LPACs to act as CSCs were analyzed. Microarray analysis was performed to reveal genes related to treatment resistance. The prognostic impact of potent genes was examined in 190 patients with colorectal cancer.
  
  
  RESULTS
  LPACs had a significantly increased capacity for radioresistance and chemoresistance (5-fluorouracil and oxaliplatin), significantly lower reactive oxygen species activity, and significantly increased sphere formation capacity compared with non-LPACs. The number of cells in the G0-G1phase was significantly higher among LPACs. Subcutaneous injection of as few as 20 LPACs led to tumor formation in immunologically incompetent mice. Microarray analysis revealed that the expression of EP300-interacting inhibitor of differentiation 3 (EID3) was significantly increased in LPACs. In vitro assay revealed that EID3 positively controlled cell proliferation and treatment resistance. The high expression of EID3 was an adverse prognostic indicator in patients with colorectal cancer (P = 0.0400).
  
  
  CONCLUSIONS
  LPACs have characteristic treatment resistance and act as CSCs in colorectal cancer. In addition, EID3 is one of the potential regulators of treatment resistance in colorectal cancer and may be a potential therapeutic target. Clin Cancer Res; 22(21); 5277-86. ©2016 AACR.
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Japan.|Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
authors.forename: Koji
authors.initials: K
authors.lastname: Munakata
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Japan. uemura7777@hotmail.com muemura@onh.go.jp.|Department of Surgery, National Hospital Organization, Osaka National Hospital, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Uemura
authors.affiliation: Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Tanaka
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kawai
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kitahara
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Miyo
authors.affiliation: Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kano
authors.affiliation: Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Japan.
authors.forename: Shinpei
authors.initials: S
authors.lastname: Nishikawa
authors.affiliation: Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Japan.
authors.forename: Takahito
authors.initials: T
authors.lastname: Fukusumi
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Takahashi
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Japan.
authors.forename: Taishi
authors.initials: T
authors.lastname: Hata
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Nishimura
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Takemasa
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Japan.
authors.forename: Tsunekazu
authors.initials: T
authors.lastname: Mizushima
authors.affiliation: Department of Surgery, Osaka Rosai Hospital, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Ikenaga
authors.affiliation: Department of Surgery, Kansai Rosai Hospital, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kato
authors.affiliation: Department of Surgery, Suita Municipal Hospital, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Murata
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
authors.forename: John M
authors.initials: JM
authors.lastname: Carethers
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Yamamoto
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Doki
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Mori
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D016193:G1 Phase / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D016192:Resting Phase, Cell Cycle / Q000187:drug effects
chemical_list: D002352:Carrier Proteins; D009944:Organoplatinum Compounds; D017382:Reactive Oxygen Species; D000077150:Oxaliplatin; D046988:Proteasome Endopeptidase Complex; D005472:Fluorouracil