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

ABSTRACT: 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.

SUBMITTER: Chen Y

PROVIDER: S-EPMC6748083 | biostudies-literature |

REPOSITORIES: biostudies-literature

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p113 isoform encoded by CUX1 circular RNA drives tumor progression via facilitating ZRF1/BRD4 transactivation.

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Circular RNA circFIRRE drives osteosarcoma progression and metastasis through tumorigenic-angiogenic coupling

Project description:Background Disappointing clinical efficacy of standard treatment has been proven in refractory metastatic osteosarcoma, and the emerging anti-angiogenic regimens are still in the infantile stage. Thus, there is an urgent need to develop novel therapeutic approach for osteosarcoma lung metastasis. Methods circFIRRE was selected from RNA-sequencing of 4 matched osteosarcoma and adjacent samples. The expression of circFIRRE was verified in clinical osteosarcoma samples and cell lines via quantitative real-time polymerase chain reaction (RT-qPCR). The effect of circFIRRE was investigated in cell lines in vitro models, ex vivo models and in vivo xenograft tumor models, including proliferation, invasion, migration, metastasis and angiogenesis. Signaling regulatory mechanism was evaluated by RT-qPCR, Western blot, RNA pull-down and dual-luciferase reporter assays. Results In this article, a novel circular RNA, circFIRRE (hsa_circ_0001944) was screened out and identified from RNA-sequencing, and was upregulated in both osteosarcoma cell lines and tissues. Clinically, aberrantly upregulated circFIRRE portended higher metastatic risk and worse prognosis in osteosarcoma patients. Functionally, in vitro, ex vivo and in vivo experiments demonstrated that circFIRRE could drive primary osteosarcoma progression and lung metastasis by inducing both tumor cells and blood vessels, we call as “tumorigenic-angiogenic coupling”. Mechanistically, upregulated circFIRRE was induced by transcription factor YY1, and partially boosted the mRNA and protein level of LUZP1 by sponging miR-486-3p and miR-1225-5p. Conclusions We identified circFIRRE as a master regulator in the tumorigenesis and angiogenesis of osteosarcoma, which could be purposed as a novel prognostic biomarker and therapeutic target for refractory osteosarcoma. Supplementary Information The online version contains supplementary material available at 10.1186/s12943-022-01624-7.

| S-EPMC9389772 | biostudies-literature

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