SPA-1 controls the invasion and metastasis of human prostate cancer
SPA-1 controls the invasion and metastasis of human prostate cancer
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DOI：
10.1111/j.1349-7006.2011.01876.x
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发表时间：
2011-04-01
期刊：
影响因子：
5.7
通讯作者：
Nakamura, Eijiro
中科院分区：
文献类型：
--
作者：
Shimizu, Yosuke;Hamazaki, Yoko;Nakamura, Eijiro
最近的研究表明，SIPA 1编码的Rap GTP酶激活蛋白SPA-1是一个候选的转移效率修饰基因在人类乳腺癌。在这项研究中，我们研究了SPA-1在人前列腺癌（CaP）中的表达和功能。CAP患者肿瘤标本的免疫组化研究显示SPA-1表达与疾病进展和转移呈正相关。在人CaP细胞系中重现了这种相关性;在SCID小鼠中很少显示转移的LNCaP表达了不可检测水平的SPA-1，而高转移性PC 3显示了丰富的SPA-1表达。此外，LNCaP中的SIPA 1转导引起显著的腹部淋巴结转移而不影响原发肿瘤的大小，而PC 3中shRNA介导的SIPA 1敲低或显性活性Rap 1突变体（Rap 1V 12）的表达抑制了转移。用SPA-1转导的LNCaP（LNCaP/SPA-1）显示出与预包被的细胞外基质（ECM）（包括胶原和纤连蛋白）的粘附减弱，这是由于缺陷的ECM介导的Rap 1激活。此外，LNCaP/SPA-1显示核Brd 4水平降低，已知其结合SPA-1，导致一系列ECM相关基因的表达降低。这些结果表明，SPA-1通过调节ECM在原发部位的表达和与ECM的相互作用，在控制人CaP转移效率中起重要作用。（Cancer Sci 2011; 102：828-836）
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. (Cancer Sci 2011; 102: 828-836)