Circular RNA circ_0000376 promotes paclitaxel resistance and tumorigenesis of non‐small cell lung cancer via positively modulating KPNA4 by sponging miR‐1298‐5p

Abstract

Background Circ_0000376 could promote non‐small cell lung cancer (NSCLC) progression; however, the role of circ_0000376 in paclitaxel (PTX) resistance of NSCLC is still unknown. Methods Quantitative real‐time polymerase chain reaction (qRT‐PCR) and western blot were applied for measuring circ_0000376, microRNA‐1298‐5p (miR‐1298‐5p), and karyopherin subunit alpha 4 (KPNA4) expression. The half inhibitory concentration (IC50) of PTX was assessed by cell counting kit‐8 assay. 5‐ethynyl‐2′‐deoxyuridine assay, wound healing assay, transwell assay, and flow cytometry were performed to measure the proliferation, migration, invasion, and apoptosis of cells. The regulatory mechanisms of circ_0000376, miR‐1298‐5p, and KPNA4 were validated by dual‐luciferase reporter assay, RNA immunoprecipitation assay, and rescue experiments. Xenograft assay was used for the functional analysis of circ_0000376 in vivo. Results Circ_0000376 and KPNA4 expressions were upregulated, while miR‐1298‐5p expression was downregulated in PTX‐resistant tissues and cells. Circ_0000376 depletion promoted PTX sensitivity and apoptosis, while suppressing the proliferation, migration, and invasion of PTX‐resistant NSCLC cells. Furthermore, circ_0000376 could modulate KPNA4 expression by sponging miR‐1298‐5p. Rescue experiments showed that miR‐1298‐5p inhibition reversed the circ_0000376 depletion‐mediated anticancer effects and PTX sensitivity. Moreover, miR‐1298‐5p inhibited PTX resistance and tumorigenesis of PTX‐resistant cells, which were abolished by KPNA4 overexpression. In addition, circ_0000376 knockdown suppressed tumor growth and enhanced PTX sensitivity in vivo. Conclusion Circ_0000376 facilitated PTX resistance and tumorigenesis of NSCLC by miR‐1298‐5p/KPNA4 axis, suggesting an underlying therapeutic strategy for NSCLC.

Extracellular Vesicles in Lung Cancer: Implementation in Diagnosis and Therapeutic Perspectives

“…Indeed, there is much evidence for circRNAs being involved in promoting tumor migration, NSCLC development, resistance to therapies, and tumorigenesis, with different pathways of molecular interaction. Through the miR377-5p/NOVA2 axis, circ_007288 promotes the development of NSCLC [ 90 ], while circ_0000376 stimulates tumorigenesis and promotes drug resistance by positively modulating the action of KPNA4 and sponging miR1298-5p [ 91 ].…”