Serum Exosomes-Based Biomarker circ_0008928 Regulates Cisplatin Sensitivity,Tumor Progression,and Glycolysis Metabolism by miR-488/ HK2 Axis in Cisplatin-Resistant Nonsmall Cell Lung Carcinoma

Abstract

Background:

Nonsmall cell lung carcinoma (NSCLC) is a major cause of cancer-related death worldwide. The resistance of NSCLC to chemical drugs, such as cisplatin (CDDP), poses a heavy burden for NSCLC therapy. Herein, the effects of circular_0008928 (circ_0008928) on the CDDP sensitivity and biological behavior of CDDP-resistant NSCLC cells and underlying mechanism are revealed.

Materials and Methods:

The expression of circ_0008928 and microRNA-488 (miR-488) was detected by quantitative real-time polymerase chain reaction. The expression of hexokinase 2 (HK2) protein and exosome-specific proteins was determined by Western blot. The half-maximal inhibitory concentration (IC₅₀) value of CDDP was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cell proliferation and migratory and invasive abilities were illustrated by cell counting kit-8 and transwell assays. Cell glycolysis metabolism was illustrated by extracellular acidification rate assay, glucose kit and lactate kit assays and Western blot analysis. The binding sites between miR-488 and circ_0008928 or HK2 were predicted by starbase or microT-CDS online database, and identified by dual-luciferase reporter and RNA immunoprecipitation assays.

Results:

Circ_0008928 expression and HK2 protein expression were significantly upregulated, while miR-488 expression was obviously downregulated in NSCLC cells and CDDP-resistant NSCLC cells. Circ_0008928 expression was increased in serum exosomes of CDDP-resistant NSCLC patients compared with CDDP-sensitive NSCLC patients. In addition, circ_0008928 silencing improved CDDP sensitivity and attenuated CDDP-induced cell proliferation, migration, invasion, and glycolysis metabolism. Circ_0008928 was a sponge of miR-488, and miR-488 bound to HK2 in CDDP-resistant NSCLC cells. Furthermore, both miR-488 inhibitor and HK2 overexpression attenuated circ_0008928 absence-mediated impacts on CDDP sensitivity and tumor process in CDDP-resistant NSCLC.

Conclusions:

Circ_0008928 knockdown improved CDDP sensitivity and hindered cell proliferation, migration, invasion, and glycolysis metabolism by miR-488/HK2 axis in CDDP-resistant NSCLC. This finding provides a new mechanism for studying CDDP-resistant therapy in NSCLC.