Zhang Le, Li Jun, Li Li, Zhang Jie, Wang Xiaodong, Yang Chuanhua, Li Yanyan, Lan Feng, Lin Ping
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.
Gastrointestinal Surgery Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, People's Republic of China.
Carcinogenesis. 2014 Jun;35(6):1330-40. doi: 10.1093/carcin/bgu017. Epub 2014 Jan 24.
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.
白细胞介素-23（IL-23）是一种与结直肠癌（CRC）相关的传统促炎白细胞介素。信号转导和转录激活因子（STAT）以及细胞因子信号抑制因子（Socs）分子分别作为IL-23相关炎症的激动剂和拮抗剂。然而，IL-23是否直接影响CRC转移仍不清楚。在本研究中，我们在体外和体内测量了几种受IL-23刺激的人CRC细胞系的转移情况。有趣的是，仅在SW-620细胞中观察到IL-23的促转移作用。IL-23相关的迁移和侵袭是由STAT5的磷酸化介导的。IL-23通过DNA甲基化和DNA甲基转移酶-1（DNMT-1）依赖性方式损害SW-620中Socs3的表达。在其他三种细胞中未观察到DNMT-1相关的调节。进一步证实Socs3在体外和体内均抑制IL-23的促转移功能。我们分析了肿瘤中IL-23水平与CRC转移之间的临床相关性，发现CRC组织中较高的IL-23水平和较低的Socs3水平导致更多的转移病例。总之，结果表明IL-23在STAT5的辅助下，可能仅促进Socs3表达缺陷的CRC转移，其中涉及IL-23诱导的DNMT-1。阐明了Socs3似乎是介导IL-23选择性的重要因素之一。综上所述，这些发现为IL-23在癌症生物学中的作用带来了新的见解，并提供了有关IL-23相关CRC治疗的额外临床前数据。
