title: xCT, component of cysteine/glutamate transporter, as an independent prognostic factor in human esophageal squamous cell carcinoma.
abstract: BACKGROUND
  xCT is a component of the cysteine/glutamate transporter, which plays a key role in glutathione synthesis. The objectives of the present study were to investigate the role of xCT in the regulation of genes involved in cell cycle progression and the clinicopathological significance of its expression in esophageal squamous cell carcinoma (ESCC).
  
  
  METHODS
  xCT expression in human ESCC cell lines was analyzed by Western blotting and immunofluorescent staining. Knockdown experiments were conducted with xCT siRNA, and the effect on cell cycle was analyzed. The cells' gene expression profiles were analyzed by microarray analysis. An immunohistochemical analysis of 70 primary tumor samples obtained from ESCC patients that had undergone esophagectomy was performed.
  
  
  RESULTS
  xCT was highly expressed in TE13 and KYSE170 cells. In these cells, the knockdown of xCT using siRNA inhibited G1-S phase progression. Microarray analysis identified 1652 genes whose expression levels in TE13 cells were altered by the knockdown of xCT. Pathway analysis showed that the top-ranked canonical pathway was the G1/S checkpoint regulation pathway, which involves TP53INP1, CDKN1A, CyclinD1/cdk4, and E2F5. Immunohistochemical staining showed that xCT is mainly found in the nuclei of carcinoma cells, and that its expression is an independent prognostic factor.
  
  
  CONCLUSIONS
  These observations suggest that the expression of xCT in ESCC cells might affect the G1/S checkpoint and impact on the prognosis of ESCC patients. As a result, we have a deeper understanding of the role played by xCT as a mediator and/or biomarker in ESCC.
authors.affiliation: Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-8566, Japan, shiozaki@koto.kpu-m.ac.jp.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Shiozaki
authors.forename: Daisuke
authors.initials: D
authors.lastname: Iitaka
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ichikawa
authors.forename: Shingo
authors.initials: S
authors.lastname: Nakashima
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Fujiwara
authors.forename: Kazuma
authors.initials: K
authors.lastname: Okamoto
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kubota
authors.forename: Shuhei
authors.initials: S
authors.lastname: Komatsu
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Kosuga
authors.forename: Hiroki
authors.initials: H
authors.lastname: Takeshita
authors.forename: Hiroki
authors.initials: H
authors.lastname: Shimizu
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Nako
authors.forename: Hisami
authors.initials: H
authors.lastname: Sasagawa
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Kishimoto
authors.forename: Eigo
authors.initials: E
authors.lastname: Otsuji
mesh_terms: D027182:Amino Acid Transport System y+ / Q000235:genetics*; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000473:pathology; D000077277:Esophageal Squamous Cell Carcinoma; D059585:G1 Phase Cell Cycle Checkpoints / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D046228:Microarray Analysis; D011379:Prognosis; D034741:RNA, Small Interfering / Q000008:administration & dosage; D059807:S Phase Cell Cycle Checkpoints / Q000235:genetics
chemical_list: D027182:Amino Acid Transport System y+; D034741:RNA, Small Interfering; C118895:SLC7A11 protein, human