卵巢癌干细胞自分泌IL-23在自我更新中的作用和机制研究

Self-renewal is the most essential characteristic of ovarian cancer stem cells (OCSCs) and autocrine signaling is involved in self-renewal of OCSCs. In our primary experiments, we found exciting results as follows: IL-23 and IL23R are upregulated in OCSCs and inhibition the function of IL-23 by three ways（antibody inhibition，STA5326，small interfering RNA-based knock-down，）could reduce the sphere number and size of OCSCs. Based on the previous results,combined with the function of NF-κB and STAT3 signaling pathway that mediate IL-23/IL-23R in cancer stem cell self-renewal. We propose that IL-23 is involved in OCSCs regulation by NF-κB and STAT3 signaling pathways. We would use neutralizing antibody, expression inhibition and lentivirus-mediated gene trasfer to knock down IL-23 to determine the role of IL-23 in OCSCs self-renewal in vitro and in vivo. Furthermore, we would elucidate the underlying mechanisms of IL-23-regulating OCSCs self-renewal by Western blot、ELISA and IF. Also, we would validate the results by samples collected from clinic patients with ovarian cancer. The present project will help to elucidate the underlying mechanisms of OCSCs self-renewal, but also provide a new avenue for OCSCs targeting therapy.

自我更新是肿瘤干细胞（CSCs）最本质的生物学特性，自分泌信号在其调控中发挥重要作用。本项目基于申请者前期发现：卵巢癌干细胞（OCSCs）高表达IL-23及IL-23R，通过采用三种不同的方法阻断IL-23/IL-23R，可明显降低OCSCs的成球数量和成球大小。结合IL-23/IL-23R介导的NF-κB和STAT3两条信号通路在CSCs自我更新作用中的认识，推测：OCSCs可能通过自分泌IL-23，活化NF-κB和/或STAT3信号通路调控其自我更新。本项目拟在前期工作的基础上，进一步在体外及荷瘤小鼠模型中明确OCSCs自分泌IL-23在维持自我更新中的作用，并且探讨IL-23通过NF-κB和/或STAT3维持其自我更新的分子机制；最终通过临床标本验证上述现象和机制。通过本研究深入了解OCSCs通过自分泌维持自我更新的分子机制，并也将为针对OCSCs的靶向治疗提供新的分子靶点。

肿瘤干细胞是具有自我更新和无限增殖能力的一类细胞，其与肿瘤转移、复发和耐药密切相关。目前研究发现炎症相关因子和趋化因子介导肿瘤干细胞的自我更新和分化能力。因此我们认为卵巢癌干细胞也能够通过炎症相关因素维持其自身的自我更新和分化能力。该项目探讨炎症相关因子白介素-23对卵巢癌干细胞自我更新的生物学作用及其具体机制。我们发现：卵巢癌干细胞在体外实验中高表达白介素-23及其受体，白介素-23能够促进卵巢癌干细胞自我更新并维持其表面干细胞标记物；进一步通过体内实验明确白介素-23能够促进卵巢癌干细胞裸鼠皮下成瘤；以上现象是通过STAT3和NF-κB两条信号通路实现的；此外，在人低分化卵巢癌组织中，白介素-23高表达并且白介素-23与CD133、Nanog和Oct4等干细胞标记物表达正相关。通过以上研究，我们证明了卵巢癌干细胞能够自分泌白介素-23促进其自我更新能力，为靶向白介素-23及其下游信号通路，治疗卵巢癌提供了依据。