title: Soluble CXCL16 in preoperative serum is a novel prognostic marker and predicts recurrence of liver metastases in colorectal cancer patients.
abstract: OBJECTIVE
  This study was designed to identify novel and reliable serum prognostic markers in patients with colorectal cancer (CRC).
  
  
  METHODS
  Based on cytokine array analysis, we identified soluble CXCL16 as a novel prognostic serum marker. Serum levels of CXCL16 were assessed in 314 CRC patients and 20 normal volunteers by enzyme-linked immunosorbent assay, and their relationships with clinicopathologic findings, including survival, were investigated. Proliferation, invasion, and wound healing assays were used to investigate the biological role of soluble CXCL16 in CRC cells, by exposure of HT-29 cells to recombinant CXCL16.
  
  
  RESULTS
  The median serum CXCL16 concentration in CRC patients was significantly higher than that in normal volunteers. In addition, serum CXCL16 levels increased significantly in accordance with the progression of UICC stage classification. Elevated serum CXCL16 level was significantly associated with poor survival and was an independent prognostic marker in CRC patients. Furthermore, in stage I-III CRC patients who underwent curative intent surgery, elevated serum CXCL16 levels were significantly associated with metachronous liver recurrence and poor survival. Recombinant soluble CXCL16 promoted the epithelial-mesenchymal transition (EMT) phenotype characterized by impaired E-cadherin production and induction of vimentin in vitro. In addition, recombinant soluble CXCL16 promoted cell growth, migration, and invasion in a CRC cell line.
  
  
  CONCLUSIONS
  In this study, we identified CXCL16 as a novel prognostic marker. Preoperative high serum levels of CXCL16 were associated with metachronous liver recurrence and poor prognosis in CRC patients. Soluble CXCL16 may play an important role in liver metastases through the induction of EMT.
authors.affiliation: Division of Reparative Medicine, Department of Gastrointestinal and Pediatric Surgery, Institute of Life Sciences, Mie University Graduate School of Medicine, Tsu, Mie, Japan. cohey@clin.medic.mie-u.ac.jp
authors.forename: Kohei
authors.initials: K
authors.lastname: Matsushita
authors.forename: Yuji
authors.initials: Y
authors.lastname: Toiyama
authors.forename: Koji
authors.initials: K
authors.lastname: Tanaka
authors.forename: Susumu
authors.initials: S
authors.lastname: Saigusa
authors.forename: Junichiro
authors.initials: J
authors.lastname: Hiro
authors.forename: Keiichi
authors.initials: K
authors.lastname: Uchida
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Inoue
authors.forename: Masato
authors.initials: M
authors.lastname: Kusunoki
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000097:blood*; D018938:Caco-2 Cells; D015820:Cadherins / Q000378:metabolism; D016022:Case-Control Studies; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D000075743:Chemokine CXCL16; D019743:Chemokines, CXC / Q000097:blood* / Q000378:metabolism / Q000494:pharmacology; D002648:Child; D015179:Colorectal Neoplasms / Q000097:blood* / Q000473:pathology* / Q000601:surgery; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005260:Female; D019073:HT29 Cells; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000097:blood* / Q000556:secondary*; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local / Q000097:blood* / Q000556:secondary; D009367:Neoplasm Staging; D057234:Preoperative Period; D000075744:Receptors, CXCR6; D019707:Receptors, Chemokine / Q000378:metabolism; D051116:Receptors, Scavenger / Q000097:blood* / Q000378:metabolism; D011991:Receptors, Virus / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D018709:Statistics, Nonparametric; D014746:Vimentin / Q000378:metabolism; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C423727:CXCL16 protein, human; C106330:CXCR6 protein, human; D015820:Cadherins; D000075743:Chemokine CXCL16; D019743:Chemokines, CXC; D000075744:Receptors, CXCR6; D019707:Receptors, Chemokine; D051116:Receptors, Scavenger; D011991:Receptors, Virus; D011994:Recombinant Proteins; D014746:Vimentin