The thioredoxin system in breast cancer cell invasion and migration.
The thioredoxin system in breast cancer cell invasion and migration.
复制标题
乳腺癌细胞入侵和迁移中的硫氧还蛋白系统。
DOI：
10.1016/j.redox.2015.12.004
复制
发表时间：
2016-08
期刊：
影响因子：
11.4
通讯作者：
Tonissen KF
中科院分区：
文献类型：
--
作者：
Bhatia M;McGrath KL;Di Trapani G;Charoentong P;Shah F;King MM;Clarke FM;Tonissen KF
转移是乳腺癌最威胁生命的方面。这是一个多步骤的过程，涉及原发性肿瘤细胞的侵袭和迁移，随后这些细胞在继发性位置定植。本研究的目的是探讨硫氧还蛋白（Trx 1）在乳腺癌细胞的侵袭和迁移中的作用，并评估高水平的Trx 1和硫氧还蛋白还原酶（TrxR 1）表达与乳腺癌患者生存率之间的相关性。我们的研究结果表明，与同一患者的配对正常乳腺组织相比，乳腺癌患者细胞中Trx 1和TrxR 1的表达在统计学上显著增加。在体外试验中，Trx 1在MDA-MB-231乳腺癌细胞系中的过表达增强了细胞侵袭，而Trx 1的氧化还原失活突变体形式（指定为1 SS）或反义mRNA的表达抑制了细胞侵袭。此外，外源性Trx 1也增强了细胞的侵袭，而添加一个特定的单克隆抗体，抑制Trx 1氧化还原功能降低细胞的侵袭。细胞内Trx 1的过度表达并不增加细胞迁移，但细胞内1 SS的表达抑制迁移。加入外源性Trx 1可增强细胞迁移，而1 SS则无此作用。用金诺芬处理抑制MDA-MB-231细胞的TrxR活性、细胞迁移和克隆形成活性，同时增加活性氧（ROS）水平。对25个独立队列5910例患者的分析显示，Trx 1和TrxR 1均与总生存率、无远处转移生存率和无疾病生存率方面的不良患者预后相关。因此，用金诺芬或其他特异性抑制剂靶向Trx系统可以通过抑制癌症侵袭和迁移来提供改善的乳腺癌患者结果。硫氧还蛋白在MDA-MB-231细胞中的过表达增强了细胞的体外侵袭。硫氧还蛋白抑制减少MDA-MB-231细胞的细胞侵袭和迁移。硫氧还蛋白的加入增强了体外MDA-MB-231细胞的迁移。金诺芬处理抑制MDA-MB-231细胞迁移和克隆形成活性。Trx 1和TrxR 1高表达与乳腺癌预后不良相关。
Metastasis is the most life threatening aspect of breast cancer. It is a multi-step process involving invasion and migration of primary tumor cells with a subsequent colonization of these cells at a secondary location. The aim of the present study was to investigate the role of thioredoxin (Trx1) in the invasion and migration of breast cancer cells and to assess the strength of the association between high levels of Trx1 and thioredoxin reductase (TrxR1) expression with breast cancer patient survival. Our results indicate that the expression of both Trx1 and TrxR1 are statistically significantly increased in breast cancer patient cells compared with paired normal breast tissue from the same patient. Over-expression of Trx1 in MDA-MB-231 breast cancer cell lines enhanced cell invasion in in vitro assays while expression of a redox inactive mutant form of Trx1 (designated 1SS) or the antisense mRNA inhibited cell invasion. Addition of exogenous Trx1 also enhanced cell invasion, while addition of a specific monoclonal antibody that inhibits Trx1 redox function decreased cell invasion. Over-expression of intracellular Trx1 did not increase cell migration but expression of intracellular 1SS inhibited migration. Addition of exogenous Trx1 enhanced cell migration while 1SS had no effect. Treatment with auranofin inhibited TrxR activity, cell migration and clonogenic activity of MDA-MB-231 cells, while increasing reactive oxygen species (ROS) levels. Analysis of 25 independent cohorts with 5910 patients showed that Trx1 and TrxR1 were both associated with a poor patient prognosis in terms of overall survival, distant metastasis free survival and disease free survival. Therefore, targeting the Trx system with auranofin or other specific inhibitors may provide improved breast cancer patient outcomes through inhibition of cancer invasion and migration. Over expression of thioredoxin in MDA-MB-231 cells enhanced cell invasion in vitro. Thioredoxin inhibition reduced cell invasion and migration of MDA-MB-231 cells. Addition of thioredoxin enhanced migration of MDA-MB-231 cells in vitro. Auranofin treatment inhibited MDA-MB-231 cell migration and clonogenic activity. High Trx1 and TrxR1 expression is associated with a poor breast cancer prognosis.