Oncogenic circRNA hsa_circ_0000190 modulates EGFR/ERK pathway in promoting NSCLC.

Lung cancers (LC) are the leading cause of cancer-related mortality worldwide, and the majority of LC are non-small cell lung carcinoma (NSCLC). Overexpressed or activated EGFR has been associated with a poor prognosis in NSCLC. We previously identified a circular non-coding RNA, hsa_circ_0000190 (C190), as a negative prognostic biomarker of LC. Here we attempted to dissect the mechanistic function of C190 and test the potential of C190 as a therapeutic target in NSCLC. C190 was upregulated in both NSCLC clinical samples and cell lines. Activation of the EGFR pathway increased C190 expression through a MAPK/ERK-dependent mechanism. Transient and stable overexpression of C190 induced ERK1/2 phosphorylation, proliferation, and migration in vitro and xenograft tumor growth in vivo. RNA sequencing and Expression2Kinases (X2K) analysis indicated that kinases associated with cell cycle and global translation are involved in C190-activated networks, including CDKs and p70S6K, which were further validated by immunoblotting. CRISPR/Cas13a-mediated knockdown of C190 decreased proliferation and migration of NSCLC cells in vitro and suppressed tumor growth in vivo. TargetScan and CircInteractome databases predicted that C190 targets CDKs by sponging miR-142-5p. Analysis of clinical LC samples showed that C190, CDK1, and CDK6 expression were significantly higher in advanced-stage LC than in early-stage LC. In summary, C190 is directly involved in EGFR-MAPK-ERK signaling and may serve as a potential therapeutic target for the treatment of NSCLC.