Nr5a2 promotes cancer stem cell properties and tumorigenesis in nonsmall cell lung cancer by regulating Nanog
Nr5a2 promotes cancer stem cell properties and tumorigenesis in nonsmall cell lung cancer by regulating Nanog
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DOI：
10.1002/cam4.1992
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发表时间：
2019-02
期刊：
影响因子：
4
通讯作者：
Ting Ye;Jingyuan Li;Zhiwei Sun;Yongli Liu;Liangsheng Kong;Shixia Zhou;Junlin Tang;Jianyu Wang;H. Xing
中科院分区：
文献类型：
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作者：
Ting Ye;Jingyuan Li;Zhiwei Sun;Yongli Liu;Liangsheng Kong;Shixia Zhou;Junlin Tang;Jianyu Wang;H. Xing
肺癌由于诊断晚、转移发生率高，死亡率最高。癌症干细胞（CSC）是具有与正常干细胞（NSC）相似的自我更新能力的癌细胞亚群。虽然CSC可能在癌症进展中发挥重要作用，但CSC自我更新的机制以及NSC和CSC自我更新之间的关系仍然难以捉摸。孤儿核受体Nr 5a 2是一种转录因子，是胚胎干细胞和诱导多能干细胞的干细胞性的调节因子。然而，Nr 5a 2是否调节肺CSC的自我更新尚不清楚。在这里，我们展示了Nr 5a 2表达升高在人肺癌中的诊断和预后价值。我们产生了小鼠LLC-SD肺癌CSC细胞模型，其中Nr 5a 2表达增强。使用LLC‐SD模型，通过短暂和稳定的siRNA干扰Nr 5a 2表达，我们为Nr 5a 2在体外维持肺CSC自我更新和干细胞特性中的调节作用提供了令人信服的证据。此外，使用同基因和原位肺移植模型，我们阐明了与Nr 5a 2促进LLC-SD自我更新相关的增强的癌症生物学特性。更重要的是，我们发现Nr 5a 2在促进LLC‐SD自我更新中的调节作用是由其直接靶点Nanog的转录激活介导的。总之，在这项研究中，我们提供了令人信服的体外和体内证据，证明Nr 5a 2可以通过Nanog的转录上调诱导肺CSC特性并促进肿瘤发生和进展。
Lung cancer has the highest mortality rate due to late diagnosis and high incidence of metastasis. Cancer stem cells (CSCs) are a subgroup of cancer cells with self‐renewal capability similar to that of normal stem cells (NSCs). While CSCs may play an important role in cancer progression, mechanisms underlying CSC self‐renewal and the relationship between self‐renewal of the NSCs and CSCs remain elusive. The orphan nuclear receptor Nr5a2 is a transcriptional factor, and a regulator of stemness of embryonic stem cells and induced pluripotent stem cells. However, whether Nr5a2 regulates the self‐renewal of lung CSCs is unknown. Here, we showed the diagnostic and prognostic values of elevated Nr5a2 expression in human lung cancer. We generated the mouse LLC‐SD lung carcinoma CSC cellular model in which Nr5a2 expression was enhanced. Using the LLC‐SD model, through transient and stable siRNA interference of Nr5a2 expression, we provided convincing evidence for a regulatory role of Nr5a2 in the maintenance of lung CSC self‐renewal and stem cell properties in vitro. Further, using the syngeneic and orthotopic lung transplantation model, we elucidated augmented cancer biological properties associated with Nr5a2 promotion of LLC‐SD self‐renewal. More importantly, we revealed that Nr5a2’s regulatory role in promoting LLC‐SD self‐renewal is mediated by transcriptional activation of its direct target Nanog. Taken together, in this study, we have provided convincing evidence in vitro and in vivo demonstrating that Nr5a2 can induce lung CSC properties and promote tumorigenesis and progression through transcriptional up‐regulation of Nanog.