Journal
CARCINOGENESIS
Volume 35, Issue 6, Pages 1330-1340Publisher
OXFORD UNIV PRESS
DOI: 10.1093/carcin/bgu017
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Funding
- Foundation from Administration of Traditional Chinese Medicine of Sichuan, People's Republic of China [2008-27]
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Interleukin-23 (IL-23) is a conventional proinflammatory IL related to colorectal carcinoma (CRC). The signal transducer and activator of transcription (STAT) and suppressors of cytokine signaling (Socs) molecules, respectively, serve as agonists and antagonists of IL-23-associated inflammation. However, it remains unknown whether IL-23 directly affects CRC metastasis. In this study, we measured the metastasis of several human CRC cell lines stimulated by IL-23 in vitro and in vivo. Interestingly, the prometastasis effect of IL-23 was observed only in SW-620 cells. IL-23-associated migration and invasion was mediated by the phosphorylation of STAT5. The expression of Socs3 in SW-620 was impaired by IL-23 via DNA methylation and DNA methyltransferase-1 (DNMT-1)-dependent way. The DNMT-1-associated regulation was not observed in the other three cells. Socs3 was further confirmed to inhibit the prometastatic function of IL-23 both in vitro and in vivo. We analyzed the clinical correlation between the level of IL-23 in tumors and the metastasis of CRC and found that higher IL-23 levels along with lower Socs3 in CRC tissues accounted for more metastatic cases. In conclusion, it was demonstrated that IL-23, assisted by STAT5, might only promote the metastasis of CRC with deficient Socs3 expression in which IL-23-induced DNMT-1 was involved. It was elucidated that Socs3 seemed to be one of the important factors that mediate the selectivity of IL-23. Taken together, these discoveries give rise to new insights into the role of IL-23 in cancer biology and provide additional preclinical data regarding IL-23-associated therapy for CRC.
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