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Research Paper|Volume 13, Issue 9|pp 13264—13286

Tumor-derived exosomal circRNA_102481 contributes to EGFR-TKIs resistance via the miR-30a-5p/ROR1 axis in non-small cell lung cancer

Bo Yang1, Fei Teng2, Liang Chang1, Jian Wang3, De-Long Liu1, Yong-Sheng Cui1, Guang-Hu Li1
  • 1Department of Thoracic Surgery, The First Hospital of Jilin University, Chaoyang, Changchun, Jilin, China
  • 2Key Laboratory for Biorheological Science and Technology of Ministry of Education, Chongqing University Cancer Hospital, Shapingba, Chongqing, China
  • 3Department of Neurovascular Surgery, The First Hospital of Jilin University, Chaoyang, Changchun, Jilin, China
* Co-first authors
Received: August 22, 2020Accepted: February 19, 2021Published: May 5, 2021
https://doi.org/10.18632/aging.203011

Copyright: © 2021 Yang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Exosomes are messengers for intercellular communication and signal transduction. Circular RNA (circRNA) abnormal expression and regulation are involved in the occurrence and development of a variety of tumors. In the present study, exosomes in the serum of five patients with non-small cell lung cancer (NSCLC) were isolated before and after EGFR-TKIs resistance, and the circRNA expression profile was screened using a circRNA microarray. The effects of the exosome circRNA_102481 on cell proliferation and apoptosis were analyzed. The interaction between miR-30a-5p and circRNA_102481 or ROR1 was predicted by starBase software, and was confirmed by RNA pull-down and dual-luciferase reporter assays. The results showed that exosomes containing circRNA_102481 were significantly up-regulated in NSCLC with EGFR-TKIs resistance (p<0.05), and that circRNA_102481 was mainly secreted by EGFR-TKIs resistance cell via exosomes (p<0.05). Both circRNA_102481 silencing and si-circRNA_102481 transported by exosomes could inhibit EGFR-TKIs resistance cell proliferation and promote cell apoptosis and circRNA_102481 overexpression could promote EGFR-TKIs sensitive cell proliferation and inhibit cell apoptosis in vitro (p<0.05). CircRNA_102481 served as a miR-30a-5p sponge to regulate ROR1 expression (p<0.05). Furthermore, the expression of circRNA_102481 in exosomes was associated with TNM stage, tumor differentiation status, brain metastasis, and PFS and OS duration. Therefore, it was concluded that tumor-derived exosomal circRNA_ 102481 could contribute to EGFR-TKIs resistance via the microRNA-30a-5p/ROR1 axis in NSCLC. Exosomal circRNA_102481 may serve as a novel diagnostic biomarker and a therapeutic target for EGFR-TKIs resistance in NSCLC.