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。,Cell Death and Differentiation

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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。
Cell Death and Differentiation ( IF 13.7 ) Pub Date : 2018-Oct-19 , DOI: 10.1038/s41418-018-0220-6
Yajun Chen ₁ , Feng Yang ₂ , Erhu Fang ₂ , Wenjing Xiao ₁ , Hong Mei ₂ , Huanhuan Li ₂ , Dan Li ₂ , Huajie Song ₂ , Jianqun Wang ₂ , Mei Hong ₂ , Xiaojing Wang _{2,

3} , Kai Huang ₃ , Liduan Zheng _{1,

3} , Qiangsong Tong _{2,

3}

Affiliation

Argonaute 2 (AGO2) 是 microRNA (miRNA) 诱导的沉默复合物的核心成分，在肿瘤发生和侵袭性中发挥着重要作用。然而，在癌症中调节 AGO2 功能的机制仍然难以捉摸。在这里，我们确定了一种由 AGO2 基因 (circAGO2) 产生的内含子环状 RNA (circRNA) 作为 AGO2-miRNA 复合物和癌症进展的新型调节因子。CircAGO2在胃癌、结肠癌、前列腺癌和神经母细胞瘤中上调，与患者预后不良有关。CircAGO2在体外和体内促进癌细胞的生长、侵袭和转移。机理研究表明，circAGO2 与人抗原 R (HuR) 蛋白发生物理相互作用，以促进其在靶基因 3'-非翻译区的激活和富集，导致 AGO2 结合减少和 AGO2/miRNA 介导的与癌症进展相关的基因沉默的抑制。临床前，慢病毒介导的靶向 circAGO2 的短发夹 RNA 可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 circAGO2 和 HuR 之间的相互作用可抑制癌细胞的肿瘤发生和侵袭性。总之，这些结果表明致癌的 circAGO2 通过促进 AGO2-miRNA 复合物的 HuR 抑制功能来驱动癌症进展。给予慢病毒介导的靶向circAGO2的短发夹RNA可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 circAGO2 和 HuR 之间的相互作用可抑制癌细胞的肿瘤发生和侵袭性。总之，这些结果表明致癌的 circAGO2 通过促进 AGO2-miRNA 复合物的 HuR 抑制功能来驱动癌症进展。给予慢病毒介导的靶向circAGO2的短发夹RNA可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 circAGO2 和 HuR 之间的相互作用可抑制癌细胞的肿瘤发生和侵袭性。总之，这些结果表明致癌的 circAGO2 通过促进 AGO2-miRNA 复合物的 HuR 抑制功能来驱动癌症进展。

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Circular RNA circAGO2 drives cancer progression through facilitating HuR-repressed functions of AGO2-miRNA complexes.

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 from AGO2 gene (circAGO2) as a novel regulator of AGO2-miRNA complexes and cancer progression. CircAGO2 is up-regulated in gastric cancer, colon cancer, prostate cancer, and neuroblastoma, and is associated with poor prognosis of patients. CircAGO2 promotes the growth, invasion, and metastasis of cancer cells in vitro and in vivo. Mechanistic studies reveal that circAGO2 physically 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 targeting circAGO2 inhibits the expression of downstream target genes, and suppresses the tumorigenesis and aggressiveness of xenografts in nude mice. In addition, blocking the interaction between circAGO2 and HuR by cell-penetrating inhibitory peptide represses the tumorigenesis and aggressiveness of cancer cells. Taken together, these results indicate that oncogenic circAGO2 drives cancer progression through facilitating HuR-repressed functions of AGO2-miRNA complexes.

更新日期：2018-10-19

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