Circular RNA circAGO2 drives cancer progression through facilitating HuR-repressed functions of AGO2-miRNA complexes
Circular RNA circAGO2 drives cancer progression through facilitating HuR-repressed functions of AGO2-miRNA complexes
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环状RNA circAGO2通过促进AGO2-miRNA复合物的HuR抑制功能来驱动癌症进展
DOI：
10.1038/s41418-018-0220-6
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发表时间：
2019-07-01
影响因子：
12.4
通讯作者：
Tong, Qiangsong
中科院分区：
文献类型：
--
作者：
Chen, Yajun;Yang, Feng;Tong, Qiangsong
Argonaute 2（AGO 2）是microRNA（miRNA）诱导沉默复合物的核心成分，在肿瘤的发生和侵袭中起着重要作用。然而，调节AGO 2在癌症中的功能的机制仍然是难以捉摸的。因此，我们发现AGO 2基因（circAGO 2）产生的一个内含子环状RNA（circRNA）是AGO 2-miRNA复合物和肿瘤进展的新调控因子，在胃癌、结肠癌、前列腺癌和神经母细胞瘤中表达上调，并与患者预后不良相关，在体外和体内均能促进癌细胞的生长、侵袭和转移。机制研究表明，circAGO 2与人抗原R（HuR）蛋白发生物理相互作用，促进其在靶基因3 '非翻译区的激活和富集，导致AGO 2结合减少，并抑制AGO 2/miRNA介导的与癌症进展相关的基因沉默。在临床前，给予靶向circAGO 2的慢病毒介导的短发夹RNA抑制下游靶基因的表达，并抑制裸鼠异种移植物的肿瘤发生和侵袭性。此外，通过细胞穿透抑制肽阻断circAGO 2和HuR之间的相互作用，可抑制癌细胞的肿瘤发生和侵袭性。综上所述，这些结果表明致癌环AGO 2通过促进AGO 2-miRNA复合物的HuR抑制功能来驱动癌症进展。
Argonaute 2 (AGO2), the core component of microRNA (miRNA)-induced silencing complex, plays a compelling role in tumorigenesis and aggressiveness. However, the mechanisms regulating the functions of AGO2 in cancer still remain elusive. Herein, we indentify one intronic circular RNA (circRNA) generated fromAGO2gene (circAGO2) as a novel regulator of AGO2-miRNA complexes and cancer progression.CircAGO2is up-regulated in gastric cancer, colon cancer, prostate cancer, and neuroblastoma, and is associated with poor prognosis of patients.CircAGO2promotes the growth, invasion, and metastasis of cancer cells in vitro and in vivo. Mechanistic studies reveal thatcircAGO2physically interacts with human antigen R (HuR) protein to facilitate its activation and enrichment on the 3’-untranslated region of target genes, resulting in reduction of AGO2 binding and repression of AGO2/miRNA-mediated gene silencing associated with cancer progression. Pre-clinically, administration of lentivirus-mediated short hairpin RNA targetingcircAGO2inhibits the expression of downstream target genes, and suppresses the tumorigenesis and aggressiveness of xenografts in nude mice. In addition, blocking the interaction betweencircAGO2and HuR by cell-penetrating inhibitory peptide represses the tumorigenesis and aggressiveness of cancer cells. Taken together, these results indicate that oncogeniccircAGO2drives cancer progression through facilitating HuR-repressed functions of AGO2-miRNA complexes.