SPA-1 controls the invasion and metastasis of human prostate cancer

Cancer Sci. 2011 Apr;102(4):828-36. doi: 10.1111/j.1349-7006.2011.01876.x. Epub 2011 Feb 25.

Abstract

Recent studies suggest that SIPA1 encoding a Rap GTPase-activating protein SPA-1 is a candidate metastasis efficiency-modifying gene in human breast cancer. In this study, we investigated the expression and function of SPA-1 in human prostate cancer (CaP). Immunohistochemical studies of tumor specimens from CaP patients revealed a positive correlation of SPA-1 expression with disease progression and metastasis. The correlation was recapitulated in human CaP cell lines; LNCaP that rarely showed metastasis in SCID mice expressed an undetectable level of SPA-1, whereas highly metastatic PC3 showed abundant SPA-1 expression. Moreover, SIPA1 transduction in LNCaP caused prominent abdominal lymph node metastasis without affecting primary tumor size, whereas shRNA-mediated SIPA1 knockdown or expression of a dominant-active Rap1 mutant (Rap1V12) in PC3 suppressed metastasis. LNCaP transduced with SPA-1 (LNCaP/SPA-1) showed attenuated adhesion to the precoated extracellular matrices (ECM) including collagens and fibronectin, due to defective ECM-medicated Rap1 activation. In addition, LNCaP/SPA-1 showed a diminished level of nuclear Brd4, which is known to bind SPA-1, resulting in reduced expression of a series of ECM-related genes. These results suggest that SPA-1 plays an important role in controlling metastasis efficiency of human CaP by regulating the expression of and interaction with ECM in the primary sites.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Cell Adhesion*
  • Disease Progression
  • Extracellular Matrix / metabolism*
  • Flow Cytometry
  • GTPase-Activating Proteins / metabolism*
  • Humans
  • Immunoenzyme Techniques
  • Lymphatic Metastasis
  • Male
  • Mice
  • Mice, SCID
  • Neoplasm Invasiveness
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / pathology*
  • Signal Transduction
  • Tumor Cells, Cultured

Substances

  • GTPase-Activating Proteins
  • SIPA1 protein, human