MicroRNA-145 suppresses cell migration and invasion in upper tract urothelial carcinoma by targeting ARF6

FASEB J. 2020 Apr;34(4):5975-5992. doi: 10.1096/fj.201902555R. Epub 2020 Feb 20.

Abstract

ADP-ribosylation factor 6 (ARF6) is a well-studied protein that is involved in multiple biological functions including cell migration and invasion. The mechanism by which ARF6 regulates the migration and invasion of upper tract urothelial carcinoma (UTUC) is still unknown. MiR-145-5p is a tumor suppressor microRNA, which is downregulated in several cancer types. We aimed to elucidate the molecular mechanism underlying the regulation of ARF6 by miR-145-5p in UTUC. ARF6 expression was observed to be higher in UTUC tissues than paired adjacent normal tissues. A reverse correlation between ARF6 and miR-145-5p was found in UTUC tissues. MiR-145-5p inhibited ARF6 expression by directly targeting its 3'-UTR. The functional studies indicated that ARF6 expression reversed the miR-145-5p-reduced tumor cell migration and invasion. Notably, miR-145-5p reduced MMP2, N-cadherin, FAK and MMP7, and elevated E-cadherin protein levels in vitro; however, the above effects were reversed by ARF6. Further, the expression of epithelial-to-mesenchymal transition (EMT) markers and cell invasion was suppressed by knocking down MMP7 in UTUC cells. These findings suggest that miR-145-5p may suppress UTUC cell motility and invasion by targeting ARF6/MMP7 through EMT.

Keywords: ARF6; MMP7; cell invasion; miR-145-5p; upper tract urothelial carcinoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADP-Ribosylation Factor 6
  • ADP-Ribosylation Factors / genetics
  • ADP-Ribosylation Factors / metabolism*
  • Aged
  • Apoptosis
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism*
  • Case-Control Studies
  • Cell Movement*
  • Cell Proliferation
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Male
  • MicroRNAs / genetics*
  • Neoplasm Invasiveness
  • Prognosis
  • Retrospective Studies
  • Survival Rate
  • Tumor Cells, Cultured
  • Urologic Neoplasms / genetics
  • Urologic Neoplasms / metabolism
  • Urologic Neoplasms / pathology*
  • Urothelium / metabolism
  • Urothelium / pathology*

Substances

  • ADP-Ribosylation Factor 6
  • Biomarkers, Tumor
  • MIRN145 microRNA, human
  • MicroRNAs
  • ADP-Ribosylation Factors
  • ARF6 protein, human