Breast cancer metastasis suppressor 1 up-regulates miR-146, which suppresses breast cancer metastasis.
Breast cancer metastasis suppressor 1 up-regulates miR-146, which suppresses breast cancer metastasis.
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DOI：
10.1158/0008-5472.can-08-3559
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发表时间：
2009-02-15
期刊：
影响因子：
11.2
通讯作者：
Welch DR
中科院分区：
文献类型：
--
作者：
Hurst DR;Edmonds MD;Scott GK;Benz CC;Vaidya KS;Welch DR
乳腺癌转移抑制因子1(BRMS1)是一种主要以核蛋白为主的蛋白质，在不同来源的多个人和小鼠癌细胞中，通过差异调节多个基因的表达，在不阻断原位肿瘤生长的情况下抑制转移。我们推测miR-146可能参与了BRMS1抑制转移的能力，因为miR-146的表达被BRMS1改变，并且因为BRMS1和miR-146都与通过核因子-κB途径的信号减少有关。实时定量逆转录-聚合酶链式反应显示，BRMS1在转移性MDA-MB-231和MDA-MB-435细胞中分别显著上调miR-146a和miR-146b 6-60倍，在MDA-MB-435细胞中上调40倍。转导miR-146a或miR-146b可下调MDAMB-231细胞表皮生长因子受体的表达，抑制体外侵袭和迁移，抑制实验性肺转移分别为69%和84%(平均值±SE：空载体=39±6，miR-146a=12±1，miR-146b=6±1)。这些结果进一步支持了最近的观点，即调节miR-146a或miR-146b的水平可能具有抑制乳腺癌转移的治疗潜力。
Breast cancer metastasis suppressor 1 (BRMS1) is a predominantly nuclear protein that differentially regulates expression of multiple genes, leading to suppression of metastasis without blocking orthotopic tumor growth in multiple human and murine cancer cells of diverse origins. We hypothesized that miR-146 may be involved in the ability of BRMS1 to supress metastasis because miR-146 expression is altered by BRMS1 and because BRMS1 and miR-146 are both associated with decreased signaling through the nuclear factor-κB pathway. BRMS1 significantly up-regulates miR-146a by 6- to 60-fold in metastatic MDA-MB-231 and MDA-MB-435 cells, respectively, and miR-146b by 40-fold in MDA-MB-435 as measured by real-time quantitative reverse transcription-PCR. Transduction of miR-146a or miR-146b into MDA-MB-231 down-regulated expression of epidermal growth factor receptor, inhibited invasion and migration in vitro, and suppressed experimental lung metastasis by 69% and 84%, respectively (mean ± SE: empty vector = 39 ± 6, miR-146a = 12 ± 1, miR-146b = 6 ± 1). These results further support the recent notion that modulating the levels of miR-146a or miR-146b could have a therapeutic potential to suppress breast cancer metastasis.