MicroRNA-375 suppresses human colorectal cancer metastasis by targeting Frizzled 8

Oncotarget. 2016 Jun 28;7(26):40644-40656. doi: 10.18632/oncotarget.9811.


microRNAs are aberrantly expressed during the development and progression of a variety of human cancers, including colorectal cancer (CRC). Of these microRNAs, microRNA-375 (miR-375) was previously observed to be downregulated in human colorectal cancer(CRC) plasma and tissues, but its functions are largely unknown. Here, we investigated the impact of miR-375 on CRC metastasis. Specifically, miR-375 expression was significantly decreased in human CRC tissues compared with their matched noncancerous tissues (NCTs), and low levels of miR-375 predicted tumor metastatic potential. The up-regulation of miR-375 suppressed colorectal cancer cell migration and invasion in vitro and reduced tumor metastases in murine models established by both orthotopic implantation and spleen injection. Furthermore, we identified Frizzled 8 (FZD8) as a direct target of miR-375 in CRC, and miR-375 negatively regulated Wnt/β-catenin signaling by suppressing FZD8. More importantly, FZD8 expression inversely correlated with overall survival in human CRC patients and is a likely independent predictor of survival. Therefore, we concluded that miR-375 functions as a tumor-suppressive microRNA by directly acting upon FZD8, which may serve as a new therapeutic target to inhibit tumor metastasis in CRC.

Keywords: FZD8; colorectal cancer; metastasis; microRNA-375.

MeSH terms

  • Animals
  • Cell Movement
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / metabolism*
  • Gene Expression Profiling
  • Humans
  • Male
  • Mice
  • Mice, Inbred BALB C
  • MicroRNAs / metabolism*
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Prognosis
  • Receptors, Cell Surface / metabolism*
  • Signal Transduction
  • Treatment Outcome
  • Up-Regulation
  • Wound Healing


  • Fzd8 protein, human
  • MIRN375 microRNA, human
  • MicroRNAs
  • Receptors, Cell Surface