Targeted induction of endogenous NKX3-1 by small activating RNA inhibits prostate tumor growth

Shancheng Ren, Moo Rim Kang, Ji Wang, Vera Huang, Robert F. Place, Yinhao Sun, Long Cheng Li

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

BACKGROUND RNA activation (RNAa) is a small RNA-mediated gene regulation mechanism by which expression of a particular gene can be induced by targeting its promoter using small double-stranded RNA also known as small activating RNA (saRNA). We used saRNA as a molecular tool to examine NKX3-1's role as a tumor suppressor and tested in vitro and in vivo antitumor effects of NKX3-1 induction by saRNA. MATERIALS AND METHODS NKX3-1 saRNA was transfected into human prostate cancer cells including LNCaP, CWR22R, PC-3, CWR22RV1, DuPro, LAPC4, and DU145. The transfected cells were used for analysis of gene expression by RT-PCR and immunoblotting, proliferation, apoptosis and cell cycle distribution. PC-3 xenograft models were established in immunocompromised mice and treated with NKX3-1 saRNA. RESULTS NKX3-1 saRNA induced NKX3-1 expression in different prostate cancer cell lines, resulting in inhibited cell proliferation and survival, cell cycle arrest and apoptotic cell death. These effects were partly mediated by NKX3-1's regulation of several downstream genes including the upregulation of p21 and p27, and the inhibition of VEGFC expression. Treatment of mouse xenograft prostate tumors with intratumoral delivery of NKX3-1 saRNA formulated in lipid nanoparticles significantly inhibited tumor growth and prolonged animal survival. CONCLUSIONS By revealing several important target genes of NKX3-1, our findings corroborated NKX3-1's role as a tumor suppressor gene through direct regulation of the cell cycle and growth/survival pathways. This study also validated the therapeutic potential of saRNA for the treatment of prostate cancer via targeted activation of tumor suppressor genes.

Original languageEnglish (US)
Pages (from-to)1591-1601
Number of pages11
JournalProstate
Volume73
Issue number14
DOIs
StatePublished - Oct 1 2013

Keywords

  • NKX3-1
  • RNAa
  • prostate cancer
  • saRNA
  • xenograft

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