Rap1GAP regulates renal cell carcinoma invasion

Cancer Lett. 2012 Jul 1;320(1):65-71. doi: 10.1016/j.canlet.2012.01.022. Epub 2012 Jan 20.


Although patients with localized and regional kidney tumors have a high survival rate, incidence of mortality significantly increases for patients with metastatic disease. It is imperative to decipher the molecular mechanisms of kidney tumor migration and invasion in order to develop effective therapies for patients with advanced cancer. Rap1, a small GTPase protein, has been implicated in cancer cell growth and invasion. Here, we profile migratory and invasive properties of commonly used renal cell carcinoma (RCC) cell lines and correlate that with expression and function of the Rap inactivator Rap1GAP. We report that levels of Rap1GAP inversely correlate with invasion but not migration. We also report that forced over-expression of Rap1GAP decreases invasion of RCC cells but does not impact their rate of proliferation. Low expression levels of Rap1GAP in RCC cells are due, at least in part, to promoter hypermethylation. Rescued expression of Rap1GAP with a demethylating drug, decitabine (5-azadC), decreases the RCC SN12C cell invasion of collagen, fibronectin, and Matrigel matrices. RCC cell lines express distinct levels of cell adhesion proteins and the forced over-expression of Rap1GAP attenuated levels of both cadherins and integrins that are known to regulate the cancer cells invasion. These results demonstrate that targeted restoration of Rap1GAP expression may serve as a potential therapeutic approach to reduce metastasis of kidney cancers.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Azacitidine / analogs & derivatives
  • Azacitidine / pharmacology
  • Cadherins / biosynthesis
  • Cadherins / genetics
  • Carcinoma, Renal Cell / genetics*
  • Carcinoma, Renal Cell / metabolism
  • Carcinoma, Renal Cell / pathology*
  • Cell Line, Tumor
  • Cell Movement / physiology
  • DNA Methylation
  • Decitabine
  • GTPase-Activating Proteins / biosynthesis*
  • GTPase-Activating Proteins / genetics*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Integrins / biosynthesis
  • Integrins / genetics
  • Kidney Neoplasms / genetics*
  • Kidney Neoplasms / metabolism
  • Kidney Neoplasms / pathology*
  • Neoplasm Invasiveness
  • Promoter Regions, Genetic
  • RNA, Small Interfering / administration & dosage
  • RNA, Small Interfering / genetics
  • Transfection


  • Cadherins
  • GTPase-Activating Proteins
  • Integrins
  • RAP1GAP protein, human
  • RNA, Small Interfering
  • Decitabine
  • Azacitidine