FLI1 exonic circular RNAs as a novel oncogenic driver to promote tumor metastasis in small cell lung cancer

Purpose: The aberrantly upregulated Friend leukemia virus integration 1 (FLI1) is closely correlated with the malignant phenotype of small cell lung cancer (SCLC). This study attempts to examine if FLI1 exonic circular RNAs (FECRs) function as a new malignant driver that determines the metastatic phenotype in SCLC. Experimental Design: The expression of FECRs was examined in SCLC tissues and serum exosomes. The oncogenic activity of FECRs was investigated in SCLC cell lines and animal xenograft studies. Finally, we explored the molecular mechanisms underlying these non-coding RNAs as a malignant driver. Results: Therapeutic comparison of CRISPR Cas9 knockout and shRNA knockdown of FLI1 identified FECRs as a new non-canonical malignant driver in SCLC. We found that FECRs were aberrantly upregulated in SCLC tissues (p<0.0001), and was positively associated with lymph node metastasis (p<0.01). Notably, serum exosomal FECR1 was associated with poor survival and clinical response to chemotherapy. Silencing of FECRs significantly inhibited the migration in two highly aggressive SCLC cell lines and reduced tumor burden in a mouse xenograft model. Mechanistically, we uncovered that FECRs sequestered and subsequently inactivated tumor suppressor microRNA miR584-3p, leading to the activation of the Rho Associated Coiled-Coil Containing Protein Kinase 1 gene (ROCK1). Conclusion: This study identifies FLI1 exonic circular RNAs as a new oncogenic driver that promotes tumor metastasis through the miR584-ROCK1 pathway. Importantly, serum exosomal FECR1 may serve as a promising biomarker to track disease progression of SCLC.

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