IL-23 selectively promotes the metastasis of colorectal carcinoma cells with impaired Socs3 expression via the STAT5 pathway

Abstract

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.

Interleukin-23 promotes the epithelial-mesenchymal transition of oesophageal carcinoma cells via the Wnt/β-catenin pathway

“…Recent investigations have demonstrated that IL-23 plays a role in tumorigenesis and acts as a potential marker of the invasion process2425262728. Here, we found that IL-23 was highly expressed in samples from OC patients, especially with the progression of malignancy.…”

“…However, the role of IL-23 in cancer is not consistent and is occasionally controversial. In some studies, IL-23 displays anti-tumour and anti-metastatic effects, whereas in others, it promotes proliferation and metastasis202122232425262728. Therefore, the elucidation of how IL-23 impacts cellular homeostasis is urgent.…”

“…Much evidence shows that IL-23 can promote proliferation and metastasis in lung, colorectal and oral cancer2425262728, however, it remains controversial whether IL-23 contributes to EMT. Clinical diagnoses show that, OC is quite prone to metastasis and formation of new vessels, but the relevant studies are scarce.…”

SOCS proteins in regulation of receptor tyrosine kinase signaling

“…Methylation-mediated down-regulation of SOCS3 has been shown to be related to the abnormal cell growth and migration in same disease, which is mediated through loss of regulation of JAK/STAT and FAK signaling [88]. Loss of SOCS3 function results in elevated STAT5 activation leading to higher metastasis in colorectal carcinoma patients [89]. SOCS3 expression is elevated in chronic myeloid leukemia (CML) and confers resistance to interferon α (IFNα) treatment [90] indicating that expression of SOCS3 is associated with disease progression.…”

Expression array analysis of the hepatocyte growth factor invasive program

“…SOCS3 downregulation in concert with CXCL1 and CXCR4 induction and IGFBP3 suppression could produce additive or synergistic motogenic signaling. Decreased SOCS3 expression also identifies a subset of PCa patients with more aggressive disease [54,55] and has a pro-metastatic role in other cancers [56,57]. DDX58 encodes an interferon-inducible mediator of inflammatory and antiviral responses associated with the NFkB and Akt pathways, and can activate or inhibit tumor cell proliferation in a context dependent manner [58,59]; the impact of HGF induction of DDX58 on PC3M invasiveness is unclear.…”