title: Deregulation of SLIT2-mediated Cdc42 activity is associated with esophageal cancer metastasis and poor prognosis.
abstract: BACKGROUND
  SLIT2, a secreted protein, has been found to inactivate Cdc42 GTPase to modulate neural cell migration. However, alteration of SLIT2-mediated Cdc42 in terms of migration regulation remains undefined in esophageal squamous cell carcinoma (ESCC).
  
  
  METHODS
  We report here in ESCC cell, animal, and clinical models that SLIT2 acts as a migration suppressor and serves as a prognostic biomarker.
  
  
  RESULTS
  The immunohistochemistry data indicated that 31.8% (49 of 154) of tumors from ESCC patients showed low expression of SLIT2 protein which correlated with poor overall survival and disease-free survival. DNA methylation analysis suggested that promoter hypermethylation is responsible for low expression of SLIT2 in ESCC. Knockdown of SLIT2 increased ESCC cell migration, while SLIT2 stable overexpression reduced cell migration. ESCC cells treated with conditioned media from cells overexpressing SLIT2 also suppressed cell migration. Importantly, silencing of SLIT2 decreased the complex formation, and thus induced Cdc42 activity and promoted membrane localization of focal adhesion kinase and Paxillin. Anti-metastatic effect of SLIT2 was confirmed in an experimental metastasis model of SLIT2 knockdown ESCC cells.
  
  
  CONCLUSIONS
  Our results provide novel evidence that low expression of SLIT2 correlates with poor prognosis and promotes metastasis in ESCC, which may be regulated by the Cdc42-mediated pathways.
authors.affiliation: *Department of Molecular Biology and Human Genetics, College of Life Science, Tzu Chi University, Hualien, Taiwan; †Department of Surgery, Chia-Yi Christian Hospital, Chiayi, Taiwan; ‡Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan; §Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan; ‖Department of Biomedical Engineering, School of Biomedical Science and Engineering, National Yang-Ming University, Taipei, Taiwan; ¶Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan; #Department of Pathology, College of Medicine, National Cheng Kung University, Tainan, Taiwan; and **Department of Surgery, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Ruo-Chia
authors.initials: RC
authors.lastname: Tseng
authors.forename: Jia-Ming
authors.initials: JM
authors.lastname: Chang
authors.forename: Jeng-Hung
authors.initials: JH
authors.lastname: Chen
authors.forename: Way-Ren
authors.initials: WR
authors.lastname: Huang
authors.forename: Yen-An
authors.initials: YA
authors.lastname: Tang
authors.forename: I-Ying
authors.initials: IY
authors.lastname: Kuo
authors.forename: Jing-Jou
authors.initials: JJ
authors.lastname: Yan
authors.forename: Wu-Wei
authors.initials: WW
authors.lastname: Lai
authors.forename: Yi-Ching
authors.initials: YC
authors.lastname: Wang
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D004938:Esophageal Neoplasms / Q000378:metabolism* / Q000473:pathology*; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008207:Lymphatic Metastasis; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D011379:Prognosis; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism*; D000098552:Slit Homolog 2 Protein
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D020764:cdc42 GTP-Binding Protein; D000098552:Slit Homolog 2 Protein