title: Interleukin-6 trans-signaling increases the expression of carcinoembryonic antigen-related cell adhesion molecules 5 and 6 in colorectal cancer cells.
abstract: BACKGROUND
  Colorectal cancer (CRC) is among the five most frequent causes for cancer-related deaths in Europe. One of the most important tumor-associated antigens for CRC is carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5), which is involved in cell adhesion, migration, anoikis, tumor invasion and metastasis. Its family member CEACAM6 is also upregulated in adenomas and carcinomas of the colon and an independent predictor of poor survival. Previous studies have reported a link between upregulation of CEACAM5 and interleukin-6 (IL-6). IL-6 plays an important role in CRC progression, and signaling is mediated via two pathways (classic and trans-signaling). However, this link could not be confirmed by other studies, and the role of IL-6 trans-signaling in the CEACAM5 upregulation has not been elucidated. Moreover, the impact of IL-6 on the expression of CEACAM6 has not yet been examined.
  
  
  METHODS
  The expression of IL-6, IL-6 receptor (IL-6R), glycoprotein (gp) 130, CEACAM5 and CEACAM6 was analyzed by RT-PCR, Western blot, flow cytometry or qPCR. Colon cell lines were incubated with IL-6 or Hyper-IL-6 (mediating IL-6 trans-signaling), and subsequently, the expression of CEACAMs was determined by qPCR or Western blot. FLLL31, an inhibitor of the phosphorylation of signal transducer and activator of transcription-3 (STAT3), was used to determine the role of STAT3 phosphorylation.
  
  
  RESULTS
  We confirmed that colon carcinoma cell lines express IL-6 and IL-6R. We observed only a weak upregulation of CEACAM5 and CEACAM6 by classic IL-6 signaling, but a strong increase by IL-6 trans-signaling. This upregulation depended on the phosphorylation of STAT3.
  
  
  CONCLUSIONS
  Our data show the upregulation of the tumor-associated antigens CEACAM5/6 by trans-signaling of the pro-inflammatory cytokine IL-6. This mechanism may contribute to the tumor-promoting role of IL-6 and could therefore be a target for therapeutic intervention in particular by specific inhibitors such as sgp130Fc.
authors.affiliation: Division of Molecular Oncology, Institute for Experimental Cancer Research, University Hospital Schleswig-Holstein, 24105, Kiel, Germany. Reinhild.Holmer@email.uni-kiel.de.
authors.forename: Reinhild
authors.initials: R
authors.lastname: Holmer
authors.affiliation: CONARIS Research Institute AG, Kiel, Germany. g.waetzig@conaris.de.
authors.forename: Georg H
authors.initials: GH
authors.lastname: Wätzig
authors.affiliation: Section Biomedical Imaging, Department of Radiology and Neuroradiology, University Hospital Schleswig-Holstein, Kiel, Germany. stiwari@email.uni-kiel.de.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Tiwari
authors.affiliation: Institute of Biochemistry, Christian-Albrechts-University, Kiel, Germany. rosejohn@biochem.uni-kiel.de.
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
authors.affiliation: Division of Molecular Oncology, Institute for Experimental Cancer Research, University Hospital Schleswig-Holstein, 24105, Kiel, Germany. hkalthoff@email.uni-kiel.de.
authors.forename: Holger
authors.initials: H
authors.lastname: Kalthoff
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism*; D015703:Antigens, CD / Q000096:biosynthesis*; D015153:Blotting, Western; D002272:Carcinoembryonic Antigen / Q000096:biosynthesis*; D015815:Cell Adhesion Molecules / Q000096:biosynthesis*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D058851:GPI-Linked Proteins / Q000096:biosynthesis; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D015703:Antigens, CD; C527875:CEACAM5 protein, human; C504117:CEACAM6 protein, human; D002272:Carcinoembryonic Antigen; D015815:Cell Adhesion Molecules; D058851:GPI-Linked Proteins; C508600:IL6 protein, human; D015850:Interleukin-6