Tai Huai-Ching, Chang An-Chen, Yu Hong-Jeng, Huang Chao-Yuan, Tsai Yu-Chieh, Lai Yu-Wei, Sun Hui-Lung, Tang Chih-Hsin, Wang Shih-Wei
Department of Urology, National Taiwan University Hospital, Taipei, Taiwan.
Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.
Oncotarget. 2014 Sep 15;5(17):7589-98. doi: 10.18632/oncotarget.2280.
Bone metastases of prostate cancer (PCa) may cause intractable pain. Wnt-1-induced secreted protein 1 (WISP-1) belongs to the CCN family (CTGF/CYR61/NOV) that plays a key role in bone formation. We found that osteoblast-conditioned medium (OBCM) stimulates migration and vascular adhesion molecule-1 (VCAM)-1 expression in human PCa (PC3 and DU145) cells. Osteoblast transfection with WISP-1 shRNA reduced OBCM-mediated PCa migration and VCAM-1 expression. Stimulation of PCa with OBCM or WISP-1 elevated focal adhesion kinase (FAK) and p38 phosphorylation. Either FAK and p38 inhibitors or siRNA abolished osteoblast-derived WISP-1-induced migration and VCAM-1 expression. Osteoblast-derived WISP-1 inhibited miR-126 expression. Moreover, miR-216 mimic reversed the WISP-1-enhanced migration and VCAM-1 expression. This study suggests that osteoblast-derived WISP-1 promotes migration and VCAM-1 expression in human PCa cells by down-regulating miR-126 expression via αvβ1 integrin, FAK, and p38 signaling pathways. Thus, WISP-1 may be a new molecular therapeutic target in PCa bone metastasis.
前列腺癌（PCa）的骨转移可能导致难以忍受的疼痛。Wnt-1诱导分泌蛋白1（WISP-1）属于CCN家族（CTGF/CYR61/NOV），在骨形成中起关键作用。我们发现成骨细胞条件培养基（OBCM）可刺激人PCa（PC3和DU145）细胞的迁移和血管细胞黏附分子-1（VCAM）-1表达。用WISP-1短发夹RNA转染成骨细胞可减少OBCM介导的PCa迁移和VCAM-1表达。用OBCM或WISP-1刺激PCa可提高黏着斑激酶（FAK）和p38的磷酸化水平。FAK和p38抑制剂或小干扰RNA（siRNA）均可消除成骨细胞来源的WISP-1诱导的迁移和VCAM-1表达。成骨细胞来源的WISP-1可抑制miR-126的表达。此外，miR-216模拟物可逆转WISP-1增强的迁移和VCAM-1表达。本研究表明，成骨细胞来源的WISP-1通过αvβ1整合素、FAK和p38信号通路下调miR-126的表达，从而促进人PCa细胞的迁移和VCAM-1表达。因此，WISP-1可能是PCa骨转移的一个新的分子治疗靶点。
