Extracellular Vesicles Derived circSH3PXD2A Inhibits Chemoresistance of Small Cell Lung Cancer by miR-375-3p/YAP1

Int J Nanomedicine. 2023 Jun 5:18:2989-3006. doi: 10.2147/IJN.S407116. eCollection 2023.

Abstract

Introduction: Small cell lung cancer (SCLC) is a subtype of lung cancer with high malignancy and poor prognosis. Rapid acquisition of chemoresistance is one of the main reasons leading to clinical treatment failure of SCLC. Studies have indicated that circRNAs participate in multiple processes of tumor progression, including chemoresistance. However, the molecular mechanisms of circRNAs driving the chemoresistance of SCLC are not well specified.

Methods: The differentially expressed circRNAs were screened by transcriptome sequencing of chemoresistant and chemosensitive SCLC cells. The EVs of SCLC cells were isolated and identified by ultracentrifugation, Western blotting, transmission electron microscopy, nanoparticle tracking analysis and EVs uptake assays. The expression levels of circSH3PXD2A in serum and EVs of SCLC patients and healthy individuals were detected by qRT‒PCR. The characteristics of circSH3PXD2A were detected by Sanger sequencing, RNase R assay, nuclear-cytoplasmic fraction assay, and fluorescence in situ hybridization assay. The mechanisms of circSH3PXD2A inhibiting SCLC progression were studied by bioinformatics analysis, chemoresistance assay, proliferation assay, apoptosis assay, transwell assay, pull-down assay, luciferase reporting assay, and mouse xenograft assay.

Results: It was identified that the circSH3PXD2A was a prominently downregulated circRNA in chemoresistant SCLC cells. The expression level of circSH3PXD2A in EVs of SCLC patients was negatively associated with chemoresistance, and the combination of EVs-derived circSH3PXD2A and serum ProGRP (Progastrin-releasing peptide) levels had better indications for DDP-resistant SCLC patients. CircSH3PXD2A inhibited the chemoresistance, proliferation, migration, and invasion of SCLC cells through miR-375-3p/YAP1 axis in vivo and in vitro. SCLC cells cocultured with EVs secreted by circSH3PXD2A-overexpressing cells exhibited decreased chemoresistance and cell proliferation.

Conclusion: Our results manifest that EVs-derived circSH3PXD2A inhibits the chemoresistance of SCLC through miR-375-3p/YAP1 axis. Moreover, EVs-derived circSH3PXD2A may serve as a predictive biomarker for DDP-resistant SCLC patients.

Keywords: YAP1; chemoresistance; circSH3PXD2A; extracellular vesicles; miR-375-3p; small cell lung cancer.

MeSH terms

  • Animals
  • Drug Resistance, Neoplasm / genetics
  • Extracellular Vesicles*
  • Humans
  • In Situ Hybridization, Fluorescence
  • Lung Neoplasms* / drug therapy
  • Lung Neoplasms* / genetics
  • Mice
  • MicroRNAs* / genetics
  • RNA, Circular / genetics
  • Small Cell Lung Carcinoma* / drug therapy
  • Small Cell Lung Carcinoma* / genetics

Substances

  • RNA, Circular
  • MIRN375 microRNA, human
  • MicroRNAs

Grants and funding

This study was supported by the Natural Science Foundation of Anhui Province (No. 2008085MH288 and 2208085MH249), the Major program of Education Department of Anhui Province (No. 2022AH040183), the Youth Fund of Anhui Cancer Hospital (No. 2020YJQN003) and the Fundamental Research Funds for the Central Universities (No. WK9110000188).