Downregulation of homeodomain-interacting protein kinase-2 contributes to bladder cancer metastasis by regulating Wnt signaling

J Cell Biochem. 2014 Oct;115(10):1762-7. doi: 10.1002/jcb.24842.


Homeodomain-interacting protein kinase-2 (Hipk2) has been shown to have important regulatory roles in cancer biology, such as cancer cell proliferation, cell cycle, and cell invasion. However, the contributions of Hipk2 to bladder cancer metastasis remain largely unknown. In the current study, we assayed the expression level of Hipk2 in bladder cancer tissues by real-time PCR, and defined its biological functions. We found that Hipk2 levels were downregulated in most bladder cancer tissues compared with adjacent normal tissues, and Hipk2 levels were remarkably decreased in metastasized tumor tissues when compared with primary tumors. SiRNA-mediated Hipk2 silencing increased bladder cancer cell invasion. Hipk2 knockdown resulted in decrease of E-cadherin expression and increase of N-cadherin and fibronectin expression, indicated that epithelial-mesenchymal transition (EMT) was induced. We further demonstrated that Hipk2 knockdown induced Wnt signaling activation and β-catenin nuclear localization. Finally, we confirmed that Hipk2 inhibition promoted EMT and subsequent cell invasion, at least in part by activating Wnt signaling. These data suggest an important role of Hipk2 in regulating metastasis of bladder cancer and implicate the potential application of Hipk2 in bladder cancer therapy.


Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus / genetics
  • Cadherins / biosynthesis
  • Cadherins / genetics
  • Carrier Proteins / antagonists & inhibitors
  • Carrier Proteins / biosynthesis
  • Carrier Proteins / genetics*
  • Cell Movement / genetics
  • Cell Proliferation / genetics
  • Down-Regulation
  • Epithelial-Mesenchymal Transition / genetics
  • Fibronectins / biosynthesis
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Neoplasm Invasiveness / genetics*
  • Neoplasm Invasiveness / pathology
  • Neoplasm Metastasis / genetics*
  • Neoplasm Metastasis / pathology
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / biosynthesis
  • Protein-Serine-Threonine Kinases / genetics*
  • RNA Interference
  • RNA, Small Interfering
  • Tumor Cells, Cultured
  • Urinary Bladder Neoplasms / genetics*
  • Urinary Bladder Neoplasms / pathology
  • Wnt Signaling Pathway / genetics*
  • beta Catenin / metabolism


  • Cadherins
  • Carrier Proteins
  • Fibronectins
  • RNA, Small Interfering
  • beta Catenin
  • HIPK2 protein, human
  • Protein-Serine-Threonine Kinases