Mechanisms of osteopontin and CD44 as metastatic principles in prostate cancer cells.
Mechanisms of osteopontin and CD44 as metastatic principles in prostate cancer cells.
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骨桥蛋白和CD44的机理作为前列腺癌细胞中的转移原理。
DOI：
10.1186/1476-4598-6-18
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发表时间：
2007-03-07
期刊：
影响因子：
37.3
通讯作者：
Chellaiah MA
中科院分区：
文献类型：
--
作者：
Desai B;Rogers MJ;Chellaiah MA
骨桥蛋白的表达水平与几种肿瘤的转移潜能相关。骨桥蛋白是αvβ3整合素的一种特性良好的配体。本研究旨在阐明骨桥蛋白/αvβ3信号通路在前列腺癌细胞迁移中的可能作用。我们建立了高表达骨桥蛋白(PC3/OPn)、整合素结合位点突变的OPN(PC3/RGDsiRNA RgA)和不表达OPn(PC3/Δ)的稳定的前列腺癌细胞(PC3/OPn)。与PC3细胞相比，PC3/OPN细胞发生了以下变化：1)多核巨细胞和RANKL表达增加；2)CD44表面表达增加，CD44/MMP-9在细胞表面的相互作用增加，条件培养液中的MMP-9活性增强，细胞迁移；3)浓缩条件培养液的免疫印迹分析显示，所有PC3细胞中的MMP-9蛋白水平相同。然而，酶谱分析表明，条件培养液中的MMP-9活性水平反映了PC3细胞系CD44的表面表达模式；4)尽管PC3细胞可以分泌基质金属蛋白酶-9和基质金属蛋白酶-2，但只有基质金属蛋白酶-9的分泌受骨桥蛋白表达的调节。在PC3/OPN(RGA)和PC3/siRNA细胞中观察到上述过程的强烈下调。经双膦酸盐(BP)处理的PC3/OPN细胞复制了PC3/OPN(RGA)和PC3/siRNA细胞中观察到的下调表达。Rho信号在CD44表面表达中起着至关重要的作用。BPS抑制甲氧戊酸途径，进而阻止一些小的GTP酶的苯丙基化。BPS对Rho GTPase活性的抑制可能是细胞表面CD44/MMP9相互作用、MMP9激活/分泌和细胞迁移下调的原因之一。综上所述，这些观察结果表明，CD44表面表达是前列腺癌细胞活化和迁移过程中的一个重要事件。参与上述信号通路的各个步骤和/或调节基质金属蛋白酶-9激活的分子是潜在的治疗靶点。
The expression level of osteopontin correlates with the metastatic potential of several tumors. Osteopontin is a well-characterized ligand for the αvβ3 integrin. The present study was undertaken to elucidate the possible role of osteopontin/αvβ3 signaling in prostate cancer cell migration. We generated stable prostate cancer cell (PC3) lines that over-express osteopontin (PC3/OPN), mutant OPN in the integrin binding-site (PC3/RGDΔRGA), and null for OPN (PC3/SiRNA). The following observations were made in PC3/OPN cells as compared with PC3 cells: 1) an increase in multinucleated giant cells and RANKL expression; 2) an increase in CD44 surface expression, interaction of CD44/MMP-9 on the cell surface, MMP-9 activity in the conditioned medium, and cell migration; 3) western blot analysis of concentrated conditioned medium exhibited equal levels of MMP-9 protein in all PC3 cells. However, zymography analysis demonstrated that the levels of MMP-9 activity in the conditioned media reflect the CD44 surface expression pattern of the PC3 cell lines; 4) although MMP-9 and MMP-2 are secreted by PC3 cells, only the secretion of MMP-9 is regulated by OPN expression. A strong down regulation of the above-mentioned processes was observed in PC3/OPN (RGA) and PC3/SiRNA cells. PC3/OPN cells treated with bisphosphonate (BP) reproduce the down-regulation observed in PC3/OPN (RGA) and PC3/SiRNA cells. Rho signaling plays a crucial role in CD44 surface expression. BPs inhibits the mevalonate pathway, which in turn, prevents the prenylation of a number of small GTPases. Attenuation of Rho GTPase activation by BPs may have contributed to the down regulation of cell surface CD44/MMP-9 interaction, MMP-9 activation/secretion, and cell migration. Taken together, these observations suggest that CD44 surface expression is an important event in the activation of MMP-9 and migration of prostate cancer cells. The various steps involved in the above mentioned signaling pathway and/or the molecules regulating the activation of MMP-9 are potential therapeutic target.
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影响因子：
4.8
作者：
Chellaiah, MA;Biswas, RS;Hruska, KA
通讯作者：
Hruska, KA
影响因子：
3.3
作者：
Chellaiah, MA;Kizer, N;Hruska, KA
通讯作者：
Hruska, KA
影响因子：
6.5
作者：
Hofmann, UB;Westphal, JR;Ruiter, DJ
通讯作者：
Ruiter, DJ
影响因子：
8.7
作者：
Bendeck, MP;Irvin, C;Giachelli, CM
通讯作者：
Giachelli, CM
影响因子：
4
作者：
Khan, Subarna A.;Cook, Amy C.;Denhardt, David T.
通讯作者：
Denhardt, David T.