SPA-1 controls the invasion and metastasis of human prostate cancer.
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.
Department of Urology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Yosuke
Y
Shimizu
Yoko
Y
Hamazaki
Masakazu
M
Hattori
Keiko
K
Doi
Naoki
N
Terada
Takashi
T
Kobayashi
Yoshinobu
Y
Toda
Toshinari
T
Yamasaki
Takahiro
T
Inoue
Yoichiro
Y
Kajita
Atsushi
A
Maeno
Tomomi
T
Kamba
Yoshiki
Y
Mikami
Toshiyuki
T
Kamoto
Tomomi
T
Yamada
Toru
T
Kanno
Kiyotsugu
K
Yoshikawa
Osamu
O
Ogawa
Nagahiro
N
Minato
Eijiro
E
Nakamura
D000818:Animals; D015153:Blotting, Western; D002448:Cell Adhesion; D018450:Disease Progression; D005109:Extracellular Matrix / Q000378:metabolism*; D005434:Flow Cytometry; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D008207:Lymphatic Metastasis; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D009687:Nuclear Proteins; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D020690:GTPase-Activating Proteins; D009687:Nuclear Proteins; C490403:SIPA1 protein, human