Niraparib restrains prostate cancer cell proliferation and metastasis and tumor growth in mice by regulating the lncRNA MEG3/miR-181-5p/GATA6 pathway

PeerJ. 2023 Nov 29:11:e16314. doi: 10.7717/peerj.16314. eCollection 2023.

Abstract

Background: Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi), have gained approval for treating patients with castration-resistant prostate cancer (CRPC). Maternally expressed gene 3 (MEG3), a long non-coding RNA (lncRNA), plays a role in inhibiting tumorigenesis through regulating DNA repair genes. This study aimed to investigate the association between the anti-prostate cancer (PCa) effect of niraparib, a representative PARPi, and MEG3 expression, as well as explore the downstream pathway involved.

Methods: The levels of MEG3, miR-181-5p, GATA binding protein 6 (GATA6) in clinical samples from PCa patients were accessed by RT-qPCR. PC3 cells were treated with niraparib, and the expression of MEG3, miR-181-5p, GATA6 expression was tested. PC3 cell proliferation, migration, and invasion were tested by CCK-8, wound healing, and Transwell assays, respectively. The bindings between miR-181-5p and MEG3/GATA6 were determined by dual-luciferase reporter gene assay. Furthermore, rescue experiments were conducted to investigate the underlying mechanism of MEG3/miR-181-5p/GATA6 axis in PCa progression. Additionally, mice were injected with PC3 cells transfected with sh-MEG3 and treated with niraparib, and the xenograft tumor growth was observed.

Results: MEG3 and GATA6 were upregulated and miR-181-5p was downregulated in PCa patients. Niraparib treatment substantially upregulated MEG3 and GATA6, and downregulated miR-181-5p expression in PCa cells. Niraparib effectively restrained PC3 cell proliferation, migration, and invasion. MiR-181-5p targeted to MEG3, and the inhibitory effects of MEG3 overexpression on PC3 cell proliferation and metastasis were abrogated by miR-181-5p overexpression. Moreover, GATA6 was identified as a target of miR-181-5p, and GATA6 silencing abolished the inhibitory effects of miR-181-5p inhibition on PC3 cell proliferation and metastasis. Besides, MEG3 silencing could abrogate niraparib-mediated tumor growth inhibition in mice.

Conclusions: Niraparib restrains prostate cancer cell proliferation and metastasis and tumor growth in mice by regulating the lncRNA MEG3/miR-181-5p/GATA6 pathway.

Keywords: GATA6; LncRNA MEG3; MiR-181-5p; Niraparib; PCa; PRAPi.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • GATA6 Transcription Factor / genetics
  • Humans
  • Male
  • Mice
  • MicroRNAs* / genetics
  • Prostatic Hyperplasia*
  • Prostatic Neoplasms* / drug therapy
  • RNA, Long Noncoding* / genetics

Substances

  • RNA, Long Noncoding
  • niraparib
  • MicroRNAs
  • GATA6 protein, human
  • GATA6 Transcription Factor
  • MIrn181 microRNA, human
  • mirn181 microRNA, mouse

Grants and funding

This work was supported by Shaanxi Natural Science Basic Research Program “Research of the invasion and metastasis mechanism mediated by LncRNA MEG3/miR-181/GATA6 axis in prostate cancer cells” (No.2023-JC-YB-796). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.