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

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.

• Authors: Yosuke Shimizu, Yoko Hamazaki, Masakazu Hattori, Keiko Doi, Naoki Terada, Takashi Kobayashi, Yoshinobu Toda, Toshinari Yamasaki, Takahiro Inoue, Yoichiro Kajita, Atsushi Maeno, Tomomi Kamba, Yoshiki Mikami, Toshiyuki Kamoto, Tomomi Yamada, Toru Kanno, Kiyotsugu Yoshikawa, Osamu Ogawa, Nagahiro Minato, Eijiro Nakamura
• Journal: Cancer science (Cancer Sci) Vol. 102 Issue 4 Pg. 828-36 (Apr 2011) ISSN: 1349-7006 [Electronic] England
• PMID: 21251160 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2011 Japanese Cancer Association.

Chemical References

• GTPase-Activating Proteins
• Nuclear Proteins
• SIPA1 protein, human

Topics

• 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
• Nuclear Proteins
• Prostatic Neoplasms (metabolism, pathology)
• Signal Transduction
• Tumor Cells, Cultured