Modulation of MicroRNA-194 and cell migration by HER2-targeting trastuzumab in breast cancer.
Modulation of MicroRNA-194 and cell migration by HER2-targeting trastuzumab in breast cancer.
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DOI：
10.1371/journal.pone.0041170
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Bast RC Jr
中科院分区：
文献类型：
--
作者：
Le XF;Almeida MI;Mao W;Spizzo R;Rossi S;Nicoloso MS;Zhang S;Wu Y;Calin GA;Bast RC Jr
曲妥珠单抗是一种针对HER 2癌蛋白胞外结构域的人源化单克隆抗体，可通过多种机制有效靶向HER 2阳性乳腺癌。虽然曲妥珠单抗对癌细胞增殖、血管生成和凋亡的影响已被深入研究，但曲妥珠单抗对microRNA（miRNA）的影响尚未被广泛研究。我们在过度表达HER 2的SKBr 3和BT474人乳腺癌细胞中进行了曲妥珠单抗治疗前后的miRNA微阵列分析。我们发现，曲妥珠单抗治疗SKBr 3细胞显着减少5个miRNA，增加其他3个，而BT474细胞显着减少2个miRNA，增加9个。曲妥珠单抗治疗后，在两种细胞系中观察到的miRNA表达的唯一变化是miRNA-194（miR-194）的上调，这在体外和体内得到了进一步验证。在过表达HER 2的乳腺癌细胞中强制表达miR-194对细胞凋亡没有影响，对增殖有适度抑制，对体外细胞迁移/侵袭有显着抑制，对体内异种移植物生长有显着抑制。相反，miR-194的敲低促进细胞迁移。miR-194表达的增加显著降低了细胞骨架蛋白talin 2的水平，并特异性抑制talin 2野生型3′-非翻译区的荧光素酶报告基因活性，但不抑制突变型报告基因的活性，表明talin 2是miR-194的直接下游靶点。曲妥珠单抗治疗抑制乳腺癌细胞迁移和减少talin 2表达在体外和体内。talin 2的敲除抑制细胞迁移/侵袭。用miR-194抑制剂敲低曲妥珠单抗诱导的miR-194表达损害了曲妥珠单抗抑制HER 2过表达乳腺癌细胞中的细胞迁移。因此，曲妥珠单抗治疗上调miR-194表达，并可能通过miR-194介导的HER 2过表达人乳腺癌细胞中细胞骨架蛋白talin 2的下调发挥其细胞迁移抑制作用。
Trastuzumab, a humanized monoclonal antibody directed against the extracellular domain of the HER2 oncoprotein, can effectively target HER2-positive breast cancer through several mechanisms. Although the effects of trastuzumab on cancer cell proliferation, angiogenesis and apoptosis have been investigated in depth, the effect of trastuzumab on microRNA (miRNA) has not been extensively studied. We have performed miRNA microarray profiling before and after trastuzumab treatment in SKBr3 and BT474 human breast cancer cells that overexpress HER2. We found that trastuzumab treatment of SKBr3 cells significantly decreased five miRNAs and increased three others, whereas treatment of BT474 cells significantly decreased two miRNAs and increased nine. The only change in miRNA expression observed in both cell lines following trastuzumab treatment was upregulation of miRNA-194 (miR-194) that was further validated in vitro and in vivo. Forced expression of miR-194 in breast cancer cells that overexpress HER2 produced no effect on apoptosis, modest inhibition of proliferation, significant inhibition of cell migration/invasion in vitro and significant inhibition of xenograft growth in vivo. Conversely, knockdown of miR-194 promoted cell migration. Increased miR-194 expression markedly reduced levels of the cytoskeletal protein talin2 and specifically inhibited luciferase reporter activity of a talin2 wild-type 3′-untranslated region, but not that of a mutant reporter, indicating that talin2 is a direct downstream target of miR-194. Trastuzumab treatment inhibited breast cancer cell migration and reduced talin2 expression in vitro and in vivo. Knockdown of talin2 inhibited cell migration/invasion. Knockdown of trastuzumab-induced miR-194 expression with a miR-194 inhibitor compromised trastuzumab-inhibited cell migration in HER2-overexpressing breast cancer cells. Consequently, trastuzumab treatment upregulates miR-194 expression and may exert its cell migration-inhibitory effect through miR-194-mediated downregulation of cytoskeleton protein talin2 in HER2-overexpressing human breast cancer cells.
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影响因子：
3.1
作者：
Cardoso, Fatima;Piccart, Martine J;Di Leo, Angelo
通讯作者：
Di Leo, Angelo
影响因子：
45.3
作者：
Cobleigh, MA;Vogel, CL;Slamon, DJ
通讯作者：
Slamon, DJ
影响因子：
7.4
作者：
Beano, Alessandra;Signorino, Elena;Matera, Lina
通讯作者：
Matera, Lina
影响因子：
64.8
作者：
Di Paolo, G;Pellegrini, L;De Camilli, P
通讯作者：
De Camilli, P
影响因子：
3.7
作者：
Ichikawa T;Sato F;Terasawa K;Tsuchiya S;Toi M;Tsujimoto G;Shimizu K
通讯作者：
Shimizu K