Abstract
BackgroundColorectal 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.MethodsThe 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.ResultsWe 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.ConclusionsOur 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1950-1) contains supplementary material, which is available to authorized users.
Highlights
Colorectal cancer (CRC) is among the five most frequent causes for cancer-related deaths in Europe
Colon cell lines express molecules mediating IL-6 signaling To understand the impact of IL-6 on colon cells, we first analyzed by reverse transcription polymerase chain reaction (RT-PCR) whether mucosa-derived colon cell lines (CSC1, NCM460) and colorectal cancer cell lines (Caco-2, HT29p, HT29c, SW480) express key components of the IL-6 signaling pathway
carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) and CEACAM6 are expressed in most colon cell lines Before we analyzed the relationship between IL-6 and carcinoembryonic antigen-related cell adhesion molecule (CEACAM), we examined the expression of CEACAM5 and CEACAM6 in the normal mucosa-derived and colorectal cancer cell lines
Summary
Colorectal cancer (CRC) is among the five most frequent causes for cancer-related deaths in Europe. IL-6 plays an important role in CRC progression, and signaling is mediated via two pathways (classic and trans-signaling). 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. The link between inflammation and tumorigenesis is exemplified by patients with colitis-associated cancer (CAC). These are CRC patients that have previously suffered from inflammatory bowel disease (IBD). It is well-known that IBD patients have a higher risk of developing CAC/CRC [4, 5]
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