Knockdown of FRAT1 expression by RNA interference inhibits human glioblastoma cell growth, migration and invasion

PLoS One. 2013 Apr 17;8(4):e61206. doi: 10.1371/journal.pone.0061206. Print 2013.

Abstract

Background: FRAT1 positively regulates the Wnt/β-catenin signaling pathway by inhibiting GSK-3-mediated phosphorylation of β-catenin. It was originally characterized as a protein frequently rearranged in advanced T cell lymphoma, but has recently also been identified as a proto-oncogene involved in tumorigenesis. Our previous studies showed that FRAT1 was dramatically overexpressed in gliomas and its expression level was significantly increased along with clinicopathological grades.

Methods: In the current study, we used RT-PCR and Western blotting to assess the mRNA and protein levels of FRAT1 in three glioma cell lines. In addition, to evaluate its functional role in gliomas, we examined the effects of FRAT1 knockdown on proliferation, migration and invasion in vitro and tumor growth in vivo using glioblastoma U251 cells and RNAi.

Results: FRAT1 was highly expressed in all three glioma cell lines. RNAi-mediated down-regulation of endogenous FRAT1 in human glioblastoma U251 cells resulted in suppression of cell proliferation, arrest of cell cycle, inhibition of cell migration and invasion in vitro. Moreover, FRAT1 depletion significantly impaired tumor xenograft growth in nude mice.

Conclusions: Our results highlight the potential role of FRAT1 in tumorigenesis and progression of glioblastoma. These findings provide a biological basis for FRAT1 as a potential molecular marker for improved pathological grading and as a novel candidate therapeutic target for glioblastoma management.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle / genetics
  • Cell Line, Tumor
  • Cell Movement / genetics*
  • Cell Proliferation
  • Cell Transformation, Neoplastic / pathology
  • Down-Regulation / genetics
  • Gene Expression Regulation, Neoplastic
  • Gene Knockdown Techniques*
  • Glioblastoma / genetics*
  • Glioblastoma / pathology*
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Mice
  • Mice, Nude
  • Neoplasm Invasiveness
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • RNA Interference*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Tumor Stem Cell Assay
  • Xenograft Model Antitumor Assays

Substances

  • FRAT1 protein, human
  • Intracellular Signaling Peptides and Proteins
  • Proto-Oncogene Proteins
  • RNA, Messenger

Grant support

This work was supported by the National Natural Science Foundation of China (No. 81201991), the Basic Research Program of Shanxi Province of China (No. 2012021035-5), the Foundation for Young Scholar of Shanxi Medical University (No. 02201116) and the Doctoral Foundation of First Hospital of Shanxi Medical University (No. YB1111).The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.