LncRNA RMRP silence curbs neonatal neuroblastoma progression by regulating microRNA-206/tachykinin-1 receptor axis via inactivating extracellular signal-regulated kinases

Cancer Biol Ther. 2019;20(5):653-665. doi: 10.1080/15384047.2018.1550568. Epub 2018 Dec 24.

Abstract

Background: Neuroblastoma is the commonest malignancy in neonates. Long non-coding RNA (lncRNA) RNA component of mitochondrial RNA processing endoribonuclease (RMRP) has been reported to be an oncogenic factor in some malignancies. However, its roles and molecular mechanisms in neuroblastoma progression are poor defined.

Methods: The expression of RMRP, microRNA-206 (miR-206), and tachykinin-1 receptor (TACR1) mRNA was measured by RT-qPCR assay. Protein levels of TACR1, phosphorylated extracellular signal-regulated kinases (ERK) 1/2 (p-ERK1/2) and ERK1/2 were detected by western blot assay. Cell proliferation was assessed by CCK-8 and colony formation assays. Cell migratory and invasive capacities were determined using Transwell migration and invasion assays. The interaction between miR-206 and RMRP or TACR1 was verified by luciferase assay. The roles and molecular mechanisms of RMRP knockdown on the growth of neuroblastoma xenografts were examined in vivo.

Results: RMRP was highly expressed in neuroblastoma tissues. RMRP knockdown inhibited proliferation, migration and invasion in neuroblastoma cells. Moreover, TACR1 was a target of miR-206 and RMRP performed as a molecular sponge of miR-206 to sequester miR-206 from TACR1 in neuroblastoma cells. TACR1 overexpression abrogated the inhibitory effect of RMRP downregulation on neuroblastoma cell progression by activating ERK1/2 pathway. Inhibition of TACR1 and ERK1/2 pathway abated RMRP-mediated pro-proliferation effect in neuroblastoma cells. RMRP knockdown hindered neuroblastoma xenograft growth by regulating miR-206/TACR1 axis via inactivating ERK1/2 pathway in vivo.

Conclusion: RMRP knockdown hindered the tumorigenesis and progression of neuroblastoma by regulating miR-206/TACR1 axis via inactivating ERK1/2 pathway, hinting a potential therapeutic target for neuroblastoma.

Keywords: RMRP; TACR1; extracellular signal-regulated kinases; microRNA-206; neuroblastoma.

MeSH terms

  • Animals
  • Carcinogenesis / genetics
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Down-Regulation
  • Female
  • Gene Expression Regulation, Neoplastic
  • Gene Knockdown Techniques
  • HEK293 Cells
  • Humans
  • Infant, Newborn
  • MAP Kinase Signaling System / genetics*
  • Male
  • Mice
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Neuroblastoma / genetics*
  • Neuroblastoma / pathology
  • RNA, Long Noncoding / genetics
  • RNA, Long Noncoding / metabolism*
  • RNA, Small Interfering / metabolism
  • Receptors, Neurokinin-1 / genetics*
  • Xenograft Model Antitumor Assays

Substances

  • MIRN206 microRNA, human
  • MicroRNAs
  • RMRP non-coding RNA, human
  • RNA, Long Noncoding
  • RNA, Small Interfering
  • Receptors, Neurokinin-1
  • TACR1 protein, human

Grant support

None