The mucosal immune response in the setting of intestinal inflammation contributes to colorectal cancer (CRC). IL-10 signaling has central role in gut homeostasis and is impaired in inflammatory bowel disease (IBD). Out of two IL-10 receptor subunits, IL-10R1 and IL-10R2, the latter is shared among the IL-10 family of cytokines and activates STAT signaling. STAT3 is oncogenic in CRC, however, knowledge about IL-10 signaling upstream of STAT3 in CRC is lacking. Here, expression of IL-10 signaling genes was examined in matched pairs from normal and tumor tissue from CRC patients showing overexpression (mRNA, protein) of IL-10R2 and STAT3 but not IL-10R1. IL-10R2 over-expression was related to microsatellite- stability. Transient overexpression of IL-10R2 in HT29 cells increased proliferation upon ligand activation (IL-10, IL-22). IL-22 and not IL-10 phosphorylated STAT3 along with increased phosphorylation of AKT and ERK. A significantly higher expression of IL-22R1 and IL-10R2 was also confirmed in separate cohort of CRC samples. IL-22 expression was elevated in gut mucosa from patients with IBD and colitis-associated cancer which also exhibited increased expression of IL-22R1 but not its co-receptor IL-10R2. Overall, these data indicate that overexpression of IL-10R2 and STAT3 contribute to colorectal carcinogenesis in microsatellite stable tumors through IL-22/STAT3 signaling.
- Received January 27, 2015.
- Revision received June 20, 2015.
- Accepted June 22, 2015.
- Copyright © 2015, American Association for Cancer Research.