RhoGDIβ promotes Sp1/MMP-2 expression and bladder cancer invasion through perturbing miR-200c-targeted JNK2 protein translation

Mol Oncol. 2017 Nov;11(11):1579-1594. doi: 10.1002/1878-0261.12132. Epub 2017 Sep 11.


Our most recent studies demonstrate that RhoGDIβ is able to promote human bladder cancer (BC) invasion and metastasis in an X-link inhibitor of apoptosis protein-dependent fashion accompanied by increased levels of matrix metalloproteinase (MMP)-2 protein expression. We also found that RhoGDIβ and MMP-2 protein expressions are consistently upregulated in both invasive BC tissues and cell lines. In the present study, we show that knockdown of RhoGDIβ inhibited MMP-2 protein expression accompanied by a reduction of invasion in human BC cells, whereas ectopic expression of RhoGDIβ upregulated MMP-2 protein expression and promoted invasion as well. The mechanistic studies indicated that MMP-2 was upregulated by RhoGDIβ at the transcriptional level by increased specific binding of the transcription factor Sp1 to the mmp-2 promoter region. Further investigation revealed that RhoGDIβ overexpression led to downregulation of miR-200c, whereas miR-200c was able directly to target 3'-UTR of jnk2mRNA and attenuated JNK2 protein translation, which resulted in attenuation of Sp1mRNA and protein expression in turn, inhibiting Sp1-dependent mmp-2 transcription. Collectively, our studies demonstrate that RhoGDIβ overexpression inhibits miR-200c abundance, which consequently results in increases of JNK2 protein translation, Sp1 expression, mmp-2 transcription, and BC invasion. These findings, together with our previous results showing X-link inhibitor of apoptosis protein mediating mRNA stabilization of both RhoGDIβ and mmp-2, reveal the nature of the MMP-2 regulatory network, which leads to MMP-2 overexpression and BC invasion.

Keywords: RhoGDIβ; bladder cancer; invasion; miR-200c.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Cell Line, Tumor
  • Down-Regulation
  • Gene Expression Regulation, Neoplastic*
  • Gene Knockdown Techniques
  • Humans
  • Matrix Metalloproteinase 2 / genetics*
  • Matrix Metalloproteinase 2 / metabolism
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Mitogen-Activated Protein Kinase 9 / genetics*
  • Mitogen-Activated Protein Kinase 9 / metabolism
  • Neoplasm Invasiveness / genetics*
  • Neoplasm Invasiveness / pathology
  • Protein Biosynthesis
  • Sp1 Transcription Factor / genetics*
  • Sp1 Transcription Factor / metabolism
  • Up-Regulation
  • Urinary Bladder Neoplasms / genetics*
  • Urinary Bladder Neoplasms / metabolism
  • Urinary Bladder Neoplasms / pathology
  • rho Guanine Nucleotide Dissociation Inhibitor beta / genetics*
  • rho Guanine Nucleotide Dissociation Inhibitor beta / metabolism


  • MIRN200 microRNA, human
  • MicroRNAs
  • Sp1 Transcription Factor
  • rho Guanine Nucleotide Dissociation Inhibitor beta
  • Mitogen-Activated Protein Kinase 9
  • Matrix Metalloproteinase 2