A Novel Serum Exosomes-Based Biomarker hsa_circ_0002130 Facilitates Osimertinib-Resistance in Non-Small Cell Lung Cancer by Sponging miR-498

Onco Targets Ther. 2020 Jun 9;13:5293-5307. doi: 10.2147/OTT.S243214. eCollection 2020.


Purpose: Exosomes are the effective delivery system for biological compounds, including circular RNAs. In this research, we aimed to explore the role of circular RNA hsa_circRNA_0002130 in osimertinib-resistant non-small cell lung cancer (NSCLC).

Materials and methods: In our study, the relative protein expression of glucose transporter 1 (GLUT1), hexokinase-2 (HK2) and lactate dehydrogenase A (LDHA) was detected by Western blot, while the expression of hsa_circ_0002130 and microRNA-498 (miR-498) was detected by quantitative real-time PCR (qRT-PCR). The biological functions of hsa_circ_0002130 in osimertinib-resistant NSCLC were analyzed by cell viability assay, flow cytometry analysis, luciferase reporter assay, RNA pull-down assay, and tumor xenograft model in vivo. Moreover, glucose uptake, lactate production and extracellular acidification (ECAR) levels were measured by glucose uptake colorimetric assay kit, lactate assay kit II, and Seahorse Extracellular Flux Analyzer XF96 assay, respectively. hsa_circ_0002130 identification and localization were confirmed by RNase R digestion and subcellular localization assay, respectively. Exosomes were isolated from the sera collected from NSCLC patients and identified using a transmission electron microscopy and nanoparticle tracking analysis.

Results: Osimertinib-resistance was closely related to glycolysis. hsa_circ_0002130 was highly expressed in osimertinib-resistant NSCLC cells and hsa_circ_0002130 deletion inhibited osimertinib-resistance both in vitro and in vivo. Moreover, hsa_circ_0002130 targeted miR-498 to regulate GLUT1, HK2 and LDHA. The inhibitory effects of hsa_circ_0002130 deletion on osimertinib-resistant were reversed by downregulating miR-498. Importantly, hsa_circ_0002130 was upregulated in serum exosomes from osimertinib-resistant NSCLC patients.

Conclusion: Our findings confirmed that hsa_circ_0002130 served as a promotion role in osimertinib-resistant NSCLC.

Keywords: GLUT1; HK2; LDHA; exosome; hsa_circ_0002130; miR-498; non-small cell lung cancer; osimertinib.

Grant support

This work was supported by the Project of Kaifeng scienceand Technology Bureau (Grant No. 1103420) and Major Science and Technology Projects of Kaifeng Science and Technology Bureau (19ZD011 and 18ZD008).