Downregulation of osteopontin contributes to metastasis suppression by breast cancer metastasis suppressor 1
Downregulation of osteopontin contributes to metastasis suppression by breast cancer metastasis suppressor 1
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DOI：
10.1002/ijc.23542
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发表时间：
2008-08-01
影响因子：
6.4
通讯作者：
Chambers, Ann F.
中科院分区：
文献类型：
--
作者：
Hedley, Benjamin D.;Welch, Danny R.;Chambers, Ann F.
乳腺癌转移抑制因子1(BRMS1)抑制多种人和小鼠癌细胞向淋巴结、骨骼和肺部转移的能力。比较转移的人癌细胞(435)和转移抑制的BRMS1细胞(435/BRMS1)的mRNA表达，发现BRMS1过表达的细胞中骨桥蛋白(OPN)的mRNA和蛋白表达显著降低(>；90%)。OPN的表达与患者的疾病进展有关，癌细胞产生的较高水平的OPN与较差的患者生存相关。此外，OPN被认为可以促进癌细胞对应激反应的存活，尽管发生这种情况的机制仍然知之甚少。本研究验证了一种假设，即OPN在转移抑制的435/BRMS1细胞中的重新表达将逆转转移抑制并提供对应激诱导的细胞凋亡的保护。建立了稳定的OPN高表达435/BRMS1细胞群(435/BRMS1/OPN)。OPN的重新表达并不影响细胞的体外生长速度；然而，观察到锚定非依赖性生长/存活的增加和对低氧诱导的细胞凋亡的保护(p<；0.05)。在体内，OPN在BRMS1转基因细胞中的重新表达并不影响体内原发肿瘤的生长，但确实增加了小鼠淋巴结和肺的自发转移的发生率。这些新的发现表明，BRMS1下调OPN可能是BRMS1通过敏化应激诱导的细胞凋亡而抑制肿瘤转移的至少部分原因。这些研究阐明了BRMS1抑制肿瘤转移的一种机制。(C)2008年Wiley-Liss，Inc.
Breast cancer metastasis suppressor 1 (BRMS1) inhibits the ability of multiple human and murine cancer cell lines to metastasize to lymph nodes, bones and lungs. Comparison of mRNA expression in metastatic MDA-MB-435 human carcinoma cells (435) and metastasis-suppressed BRMS1 transfectants (435/BRMS1) showed a marked (>90%) reduction of osteopontin (OPN) mRNA and protein expression in BRMS1-overexpressing cells. OPN expression is associated with disease progression in patients, with higher levels of OPN produced by cancer cells associated with poorer patient survival. Furthermore, OPN has been suggested to promote survival of cancer cells in response to stress, although the mechanisms by which this may occur remain poorly understood. This study tested the hypothesis that re-expression of OPN in metastasis-suppressed 435/BRMS1 cells would reverse metastasis suppression and confer protection from stress-induced apoptosis. A stable pooled population of OPN overexpressing 435/BRMS1 cells was created (435/BRMS1/OPN). OPN re-expression did not affect in vitro cell growth rates; however, increased anchorage independent growth/survival and protection from hypoxia-induced apoptosis was observed (p < 0.05). In vivo, OPN re-expression in BRMS1 transfected cells did not affect in vivo primary tumor growth but did increase the incidence of spontaneous metastasis to lymph nodes and lungs in mice. These novel findings suggest that OPN downregulation by BRMS1 may be responsible, at least in part, for BRMS1-mediated metastasis suppression by sensitizing cancer cells to stress induced apoptosis. These studies clarify one mechanism by which BRMS1 can suppress metastasis. (C) 2008 Wiley-Liss, Inc.