IL-23 selectively promotes the metastasis of colorectal carcinoma cells with impaired Socs3 expression via the STAT5 pathway.
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.
Division of Geriatrics, Center for Medical Stem Cell Biology, State Key Laboratory of Biotherapy and Gastrointestinal Surgery Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, People's Republic of China.
Le
L
Zhang
Division of Geriatrics, Center for Medical Stem Cell Biology, State Key Laboratory of Biotherapy and Gastrointestinal Surgery Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, People's Republic of China.
Jun
J
Li
Gastrointestinal Surgery Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, People's Republic of China.
Li
L
Li
Division of Geriatrics, Center for Medical Stem Cell Biology, State Key Laboratory of Biotherapy and Gastrointestinal Surgery Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, People's Republic of China.
Jie
J
Zhang
Gastrointestinal Surgery Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, People's Republic of China.
Xiaodong
X
Wang
Gastrointestinal Surgery Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, People's Republic of China.
Chuanhua
C
Yang
Division of Geriatrics, Center for Medical Stem Cell Biology, State Key Laboratory of Biotherapy and Gastrointestinal Surgery Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, People's Republic of China.
Yanyan
Y
Li
Division of Geriatrics, Center for Medical Stem Cell Biology, State Key Laboratory of Biotherapy and Gastrointestinal Surgery Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, People's Republic of China.
Feng
F
Lan
Division of Geriatrics, Center for Medical Stem Cell Biology, State Key Laboratory of Biotherapy and Gastrointestinal Surgery Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, People's Republic of China linping8@yahoo.com.
Ping
P
Lin
D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D019175:DNA Methylation; D004195:Disease Models, Animal; D015870:Gene Expression; D006801:Humans; D053759:Interleukin-23 / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D051379:Mice; D009362:Neoplasm Metastasis; D010766:Phosphorylation / Q000187:drug effects; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics* / Q000378:metabolism
D053759:Interleukin-23; C106644:SOCS3 protein, human; D050799:STAT5 Transcription Factor; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases