The circRNA circPTPRA suppresses epithelial-mesenchymal transitioning and metastasis of NSCLC cells by sponging miR-96-5p

EBioMedicine. 2019 Jun:44:182-193. doi: 10.1016/j.ebiom.2019.05.032. Epub 2019 May 31.

Abstract

Background: Non-small cell lung carcinomas (NSCLC) are prevalent, lethal cancers with especially grim prospects due to late-stage detection and chemoresistance. Circular RNAs (circRNAs) are non-coding RNAs that participate in tumor development. However, the role of circRNAs in NSCLC is not well known. This study investigated the role of one circRNA - circPTPRA- in NSCLC and characterized its molecular mechanism of action.

Methods: circPTPRA expression was analyzed in human NSCLC tumors and matched healthy lung tissue. We performed functional characterization in NSCLC cell lines and a mouse xenograft model of NSCLC to elucidate the molecular role of circPTPRA in epithelial-mesenchymal transitioning (EMT). We also assessed the regulatory action of circPTPRA on the microRNA miR-96-5p and its target the tumor suppressor Ras association domain-containing protein 8 (RASSF8).

Findings: circPTPRA was significantly downregulated in NSCLC tumors relative to matched healthy lung tissue. Lower circPTPRA levels correlated with metastasis and inferior survival outcomes in NSCLC patients. circPTPRA suppressed EMT in NSCLC cell lines and reduced metastasis in the murine xenograft model by sequestering miR-96-5p and upregulating RASSF8. Correlation analyses in patient-derived NSCLC tumor specimens supported the involvement of the circPTPRA/miR-96-5p/RASSF8/E-cadherin axis dysregulation in NSCLC tumor progression.

Interpretation: circPTPRA suppresses EMT and metastasis of NSCLC cell lines by sponging miR-96-5p, which upregulates the downstream tumor suppressor RASSF8. The circPTPRA/miR-96-5p/RASSF8/E-cadherin axis can be leveraged as a potential treatment avenue in NSCLC. FUND: The Key research and development projects of Anhui Province (201904a0720079), the Natural Science Foundation of Anhui Province (1908085MH240), the Graduate Innovation Program of Bengbu Medical College (Byycx1843), the National Natural Science Foundation of Tibet (XZ2017ZR-ZY033) and the Science and Technology Project of Shannan (SNKJYFJF2017-3) and Academic Subsidy Project for Top Talents in Universities of Anhui in 2019 (gxbjZD16).

Keywords: Epithelial-mesenchymal transition, EMT; Lung cancer; NSCLC; circRNA; miR-96-5p.

MeSH terms

  • Animals
  • Cadherins / genetics
  • Cadherins / metabolism
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / mortality
  • Carcinoma, Non-Small-Cell Lung / pathology*
  • Carcinoma, Non-Small-Cell Lung / therapy
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Cell Proliferation / genetics
  • Epithelial-Mesenchymal Transition / genetics*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • In Situ Hybridization, Fluorescence
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / mortality
  • Lung Neoplasms / pathology*
  • Lung Neoplasms / therapy
  • Mice
  • MicroRNAs / genetics*
  • Neoplasm Metastasis
  • Neoplasm Staging
  • Phenotype
  • RNA Interference
  • RNA, Circular / genetics*
  • Receptor-Like Protein Tyrosine Phosphatases, Class 4 / genetics*

Substances

  • Cadherins
  • MIRN96 microRNA, human
  • MicroRNAs
  • RNA, Circular
  • PTPRA protein, human
  • Receptor-Like Protein Tyrosine Phosphatases, Class 4