STAT3 and sphingosine-1-phosphate in inflammation-associated colorectal cancer

Abstract

Accumulated evidences have demonstrated that signal transducer and activator of transcription 3 (STAT3) is a critical link between inflammation and cancer. Multiple studies have indicated that persistent activation of STAT3 in epithelial/tumor cells in inflammation-associated colorectal cancer (CRC) is associated with sphingosine-1-phosphate (S1P) receptor signaling. In inflammatory response whereby interleukin (IL)-6 production is abundant, STAT3-mediated pathways were found to promote the activation of sphingosine kinases (SphK1 and SphK2) leading to the production of S1P. Reciprocally, S1P encourages the activation of STAT3 through a positive autocrine-loop signaling. The crosstalk between IL-6, STAT3 and sphingolipid regulated pathways may play an essential role in tumorigenesis and tumor progression in inflamed intestines. Therapeutics targeting both STAT3 and sphingolipid are therefore likely to contribute novel and more effective therapeutic strategies against inflammation-associated CRC.

Keywords: Sphingosine-1-phosphate; Signal transducer and activator of transcription 3; Interleukin-6; Inflammation; Colorectal cancer; Tumorigenesis; Tumor progression; Inflammatory bowel disease

Core tip: Patients with inflammatory bowel diseases have a predisposition for the development of colorectal cancer (CRC). We summarize current literature on the interleukin (IL)-6/signal transducer and activator of transcription 3 (STAT3) inflammatory pathway and its association with CRC. Recent papers within the last couple of years have demonstrated the crosstalk between IL-6, STAT3 and sphingosine-1-phosphate pathways in inflammation associated tumorigenesis in intestine. This signaling cascade in tumor cells appears to be an essential pathway for CRC tumor progression. Current therapies exploiting sphingolipid signaling have provided an attractive strategy against inflammation-associated CRC.