β2-microglobulin is a signaling and growth-promoting factor for human prostate cancer bone metastasis
β2-microglobulin is a signaling and growth-promoting factor for human prostate cancer bone metastasis
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DOI：
10.1158/0008-5472.can-06-1996
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发表时间：
2006-09-15
期刊：
影响因子：
11.2
通讯作者：
Chung, Leland W. K.
中科院分区：
文献类型：
--
作者：
Huang, Wen-Chin;Wu, Daqing;Chung, Leland W. K.
从人前列腺癌细胞株的条件培养液中提纯的蛋白因子β2微球蛋白(β2M)通过激活环腺苷酸(CAMP)依赖的蛋白激酶A信号通路，促进人前列腺癌细胞的生长，并增强骨钙素(OC)和骨涎蛋白(BSP)基因的表达。当β2M在前列腺癌细胞中过表达时，通过增加磷酸化的cAMP反应元件结合蛋白(CREB)并激活CREB靶基因的表达，包括OC、BSP、细胞周期蛋白A、细胞周期蛋白D1和血管内皮生长因子，从而诱导小鼠骨骼肿瘤的爆炸性生长。通过注射β2M小干扰RNA脂质体复合体阻断β2M下游信号通路，通过免疫组织化学和caspase-9、caspase-3的激活以及聚(ADP-核糖)聚合酶的裂解，增加了小鼠骨中先前建立的前列腺癌的凋亡，从而有效地逆转了先前建立的小鼠前列腺癌。这些结果表明，β2m信号通路是治疗前列腺癌骨转移的一个有吸引力的新靶点。
The protein factor beta 2-microglobulin (beta 2M), purified from the conditioned medium of human prostate cancer cell lines, stimulated growth and enhanced osteocalcin (OC) and bone sialoprotein (BSP) gene expression in human prostate cancer cells by activating a cyclic AMP (cAMP)-dependent protein kinase A signaling pathway. When beta 2M was overexpressed in prostate cancer cells, it induced explosive tumor growth in mouse bone through increased phosphorylated cAMP-responsive element binding protein (CREB) and activated CREB target gene expression, including OC, BSP, cyclin A, cyclin D1, and vascular endothelial growth factor. Interrupting the beta 2M downstream signaling pathway by injection of the beta 2M small interfering RNA liposome complex produced an effective regression of previously established prostate tumors in mouse bone through increased apoptosis as shown by immunohistochemistry and activation of caspase-9, caspase-3, and cleavage of poly(ADP-ribose) polymerase. These results suggest that beta 2M signaling is an attractive new therapeutic target for the treatment of lethal prostate cancer bone metastasis.