Abstract
BackgroundChemoresistance limits the therapeutic effect of cisplatin (DDP) on non-small cell lung cancer (NSCLC). Circular RNAs (circRNAs) function as important regulators in chemoresistance. This study aimed to explore the regulation of circRNA Phosphatidylinositol-4-Phosphate 5-Kinase Type 1 Alpha (circ_PIP5K1A) in DDP resistance.MethodsThe expression analysis of circ_PIP5K1A, micoRNA-493-5p (miR-493-5p) and Rho Associated Coiled-Coil Containing Protein Kinase 1 (ROCK1) was conducted through reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Cell sensitivity was determined using 3-(4,5-dimethylthiazol-2-y1)-2,5-diphenyl tetrazolium bromide (MTT) assay. Cell proliferation and cell viability were evaluated by colony formation assay and MTT assay, respectively. Cell cycle and apoptosis detection was performed via flow cytometry. Cell motility was examined by transwell migration or invasion assay. Dual-luciferase reporter assay was applied to confirm the target binding. ROCK1 protein level was assayed via Western blot. In vivo assay was carried out using xenograft model in mice.ResultsCirc_PIP5K1A level was abnormally increased in DDP-resistant NSCLC tissues and cells. Silencing circ_PIP5K1A reduced DDP resistance, proliferation, cell cycle progression and cell motility in DDP-resistant NSCLC cells. Circ_PIP5K1A directly interacted with miR-493-5p in NSCLC cells. The function of circ_PIP5K1A was dependent on the negative regulation of miR-493-5p. MiR-493-5p directly targeted ROCK1 and circ_PIP5K1A regulated the ROCK1 level via acting as a sponge of miR-493-5p. Overexpression of miR-493-5p inhibited chemoresistance and cancer progression by downregulating ROCK1 expression in DDP-resistant NSCLC cells. Circ_PIP5K1A regulated DDP sensitivity in vivo via the miR-493-5p/ROCK1 axis.ConclusionThese findings suggested that circ_PIP5K1A upregulated the ROCK1 expression to promote DDP resistance and cancer progression in NSCLC by sponging miR-493-5p.
Highlights
Chemoresistance limits the therapeutic effect of cisplatin (DDP) on non-small cell lung cancer (NSCLC)
Circ_PIP5K1A was upregulated in DDP‐resistant NSCLC tissues and cells Cell viability analysis showed that IC50 value was higher in A549/DDP (IC50 = 24.530) and H460/DDP
The results of reverse transcription-quantitative polymerase chain reaction (RT-qPCR) assay demonstrated that circ_PIP5K1A expression was obviously increased in tumor-resistant tissues relative to tumor-sensitive tissues (P < 0.001) and A549/DDP or H460/DDP cells compared with the A549 or H460 cells (P < 0.001, P = 0.001) (Fig. 1C, D)
Summary
Chemoresistance limits the therapeutic effect of cisplatin (DDP) on non-small cell lung cancer (NSCLC). Circular RNAs (circRNAs) function as important regulators in chemoresistance. This study aimed to explore the regulation of circRNA Phosphatidylinositol-4-Phosphate 5-Kinase Type 1 Alpha (circ_PIP5K1A) in DDP resistance. Cisplatin (DDP) is an effective chemotherapeutic drug for various kinds of cancer, but drug resistance usually leads to treatment failure [2]. Circular RNAs (circRNAs) play important roles in cancer biology by functioning as molecular sponges of microRNAs (miRNAs) and inducing expression changes of downstream genes [4, 5]. CircRNA Phosphatidylinositol-4-Phosphate 5-Kinase Type 1 Alpha (circ_PIP5K1A, hsa_circ_0014130) contributed to the malignant progression of colon cancer via sponging miR-1273a [6] and promoted the developing process of gastric cancer by the miR-376c-3p/zinc finger protein 146 (ZNF146) network [7]. The potential effect of circ_PIP5K1A on DDP resistance in NSCLC is still unclear
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