Microarray Identifies a Key Carcinogenic Circular RNA 0008594 That Is Related to Non-Small-Cell Lung Cancer Development and Lymph Node Metastasis and Promotes NSCLC Progression by Regulating the miR-760-Mediated PI3K/AKT and MEK/ERK Pathways

Abstract

PurposeThis study aimed to explore the circular RNA (circRNA/circ) profile engaged in non-small cell lung cancer (NSCLC) development and metastasis and to investigate potentially key carcinogenic circRNAs related to NSCLC.MethodsCircRNA profiles between 10 NSCLC tissues and 10 adjacent tissues and between five NSCLC tissues with lymph node metastasis (LNM) and five NSCLC tissues without LNM were detected by Arraystar Human circRNA Array followed by bioinformatics. Circ_0008594 knockdown, circ_0004293 overexpression, and circ_0003832 overexpression plasmids were transfected into H23 and H460 cells to sort potential oncogenic circRNA. Then circ_0008594 overexpression and knockdown plasmids were transfected, followed by that circ_0008594 knockdown plus miR-760 knockdown plasmids were transfected into these cells. Cell proliferation, apoptosis, invasion, stemness, and pathways were detected. In addition, xenograft mice models were constructed via injecting H23 cells with circ_0008594 overexpression or knockdown to validate the findings.ResultsA total of 455 dysregulated circRNAs in NSCLC tissues versus adjacent tissues and 353 dysregulated circRNAs in NSCLC tissues with LNM versus those without LNM were discovered. Via cross-analysis, 19 accordant circRNAs were uncovered, among which three candidate circRNAs (circ_0008594, circ_0004293, circ_0003832) were chosen for functional experiments, during which it was observed that circ_0008549 affected H23 and H460 cell proliferation and apoptosis more obviously than circ_0004293 and circ_0003832. Subsequent experiments showed that circ_0008594 promoted H23 and H460 cell proliferation and invasion but affected stemness less and negatively regulated miR-760 via direct binding. Furthermore, miR-760 attenuated the effect of circ_0008549 on regulating H23 and H460 cell functions and the PI3K/AKT and MEK/ERK pathways. In vivo experiments further confirmed that circ_0008549 increased tumor volume, epithelial-mesenchymal transition, and the PI3K/AKT and MEK/ERK pathways while reducing tumor apoptosis and miR-760 NSCLC xenograft models.ConclusionOur study identifies several valuable circRNAs related to NSCLC development and LNM. Furthermore, as a key functional circRNA, circ_0008594 was observed to promote NSCLC progression by regulating the miR-760-mediated PI3K/AKT and MEK/ERK pathways.

RETRACTED ARTICLE: Circ_0017639 facilitates proliferative, migratory, and invasive potential of non-small cell lung cancer (NSCLC) cells via PI3K/AKT signaling pathway

“…The signaling cascade i.e ., PI3K/AKT is associated with the metastasis of lung carcinoma and regulating the progression of cancerous cells [ 16–18 ]. Although PI3K/AKT cascade is critical mediators of NSCLC, for example, circular RNA 0008594 regulates NSCLC development via PI3K/AKT [ 19 ], whether circ_0017639 regulates these axes in NSCLC requires additional investigation.…”

CircRAB11A act as miR-24-5p sponge promotes proliferation and resists apoptosis of chicken granulosa cell via EGFR/ERK1/2 and RAB11A/ PI3K/AKT pathways

“…The ERK1/2 and PI3K/AKT cascade control the intracellular processes that are often involved in the regulation of circRNAs. For instance, circ-0008594 affects non-small-cell lung cancer ( NSCLC ) growth and lymph node metastasis and accelerates NSCLC progression by controlling the miR-760-mediated PI3K/AKT and MEK/ERK1/2 pathways ( Wang et al, 2021 ). Mechanically, circCDYL2 preserved the activity of the downstream AKT and ERK1/2 by stopping the ubiquitination degradation of GRB7 and improving its interaction with FAK ( Ling et al, 2022 ).…”

The postoperative prognosis of skip-N2 metastasis is favorable in small-cell lung carcinoma patients with pathological N2 classification: a propensity-score-adjusted retrospective multicenter study

“…For example, the high expression of synaptonemal complex protein 3, long non-coding RNA HOTAIR, and circular RNA 0008594 in primary tumor tissues were confirmed to promote tumor cells to metastasize to lymph nodes. [20][21][22] Another profound study mainly revealed that tumor cells needed to undergo a metabolic shift toward fatty acid oxidation before lymph node metastasis. 23 Several bioactive bile acids accumulated in lymph nodes and could activate the yes-associated protein pathway to regulate lymph node metastasis.…”