title: Prognostic significance of TWEAK expression in colorectal cancer and effect of its inhibition on invasion.
abstract: BACKGROUND
  Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) has been implicated in tumor development and progression. The aim of this study was to investigate the role of TWEAK in colorectal cancer (CRC) progression.
  
  
  METHODS
  To investigate the involvement of TWEAK in the progression of human CRC, normal, and tumor specimens from 174 patients were analyzed immunohistochemically for the expression of TWEAK. TWEAK recombinant protein treatment, transfection of expression plasmids, and small interfering RNA to knockdown TWEAK expression were performed to test invasive ability with a Boyden chamber. The mRNA expression profile in recombinant TWEAK treatment was compared to a control group by microarray analysis. To identify downstream effectors, Raf kinase inhibitor (RKIP) and its correlation with TWEAK in vitro and in vivo were examined by quantitative real-time polymerase chain reaction and invasion assays.
  
  
  RESULTS
  CRC patients whose tumors displayed high TWEAK expression had a statistically significantly higher overall survival and a disease-free advantage over those with a low TWEAK expression. In in vitro invasion assays, alterations in TWEAK expression in CRC cell lines inversely modulated their invasive ability. By means of integrated genomics, we identified RKIP as a downstream effector in TWEAK-mediated invasion inhibition. Knockout of RKIP expression in HCT116 cells by short hairpin RNA (shRKIP) resulted in increased invasiveness. Clinically, RKIP and TWEAK mRNA expression showed strong positive correlations in CRC patient samples.
  
  
  CONCLUSIONS
  Our results implicate TWEAK as a key regulator of CRC invasion, and it appears to be a useful prognostic factor for patients with CRC.
authors.affiliation: Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Been-Ren
authors.initials: BR
authors.lastname: Lin
authors.forename: Miao-Tzu
authors.initials: MT
authors.lastname: Huang
authors.forename: Szu-Ta
authors.initials: ST
authors.lastname: Chen
authors.forename: Yung-Ming
authors.initials: YM
authors.lastname: Jeng
authors.forename: Yue-Ju
authors.initials: YJ
authors.lastname: Li
authors.forename: Jin-Tung
authors.initials: JT
authors.lastname: Liang
authors.forename: Po-Huang
authors.initials: PH
authors.lastname: Lee
authors.forename: King-Jen
authors.initials: KJ
authors.lastname: Chang
authors.forename: Cheng-Chi
authors.initials: CC
authors.lastname: Chang
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D000074049:Cytokine TWEAK; D018572:Disease-Free Survival; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D005260:Female; D055786:Gene Knockout Techniques; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D049488:Phosphatidylethanolamine Binding Protein / Q000235:genetics / Q000378:metabolism*; D010957:Plasmids; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D014162:Transfection; D048069:Tumor Necrosis Factors / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D000074049:Cytokine TWEAK; C511482:PEBP1 protein, human; D049488:Phosphatidylethanolamine Binding Protein; C109743:TNFSF12 protein, human; D048069:Tumor Necrosis Factors