Low molecular weight protein tyrosine phosphatase isoforms regulate breast cancer cells migration through a RhoA dependent mechanism.
Low molecular weight protein tyrosine phosphatase isoforms regulate breast cancer cells migration through a RhoA dependent mechanism.
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DOI：
10.1371/journal.pone.0076307
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Coelho C
中科院分区：
文献类型：
--
作者：
Alho I;Costa L;Bicho M;Coelho C
低分子量蛋白酪氨酸磷酸酶（LMW-PTP）通过生长因子受体如PDGF-R和EphA 2的去磷酸化和失活与细胞增殖控制相关，并通过p190 RhoGap和RhoA与细胞粘附和迁移相关。我们的目的是阐明两种主要的LMW-PTP亚型在乳腺癌发生中的作用。我们在MDA-MB-435乳腺癌细胞系中使用siRNA介导的功能丧失来研究两种主要的LMW-PTP同工型（快型和慢型）在乳腺癌肿瘤发生和迁移中的作用。我们的研究结果表明，针对总LMW-PTP和LMW-PTP慢亚型的siRNA增强了侵袭性乳腺癌细胞系MDA-MB-435中的细胞运动性，而细胞的增殖和侵袭潜力没有变化。总LMW-PTP敲低引起细胞迁移更明显的增加。抑制总LMW-PTP降低RhoA活化，抑制LMW-PTP慢亚型引起RhoA活化的小但显著的增加。我们认为RhoA激活的增加或减少会引起应力纤维形成的变化，从而改变细胞的粘附和迁移能力。这些研究结果表明，LMW-PTP的两种主要亚型可能发挥差异作用，快速亚型在肿瘤细胞迁移中具有更突出的作用。此外，我们的研究结果突出了LMW-PTP异构体之间的功能特异性，表明这些蛋白质在乳腺癌生物学中的未知作用。应研究靶向LMW-PTP的新治疗方法，考虑这两种亚型的表达，而不是LMW-PTP作为一个整体。
Low molecular weight protein tyrosine phosphatase (LMW-PTP) has been associated with cell proliferation control through dephosphorylation and inactivation of growth factor receptors such as PDGF-R and EphA2, and with cellular adhesion and migration through p190RhoGap and RhoA. We aim to clarify the role of two main LMW-PTP isoforms in breast cancer tumorigenesis. We used a siRNA-mediated loss-of-function in MDA-MB-435 breast cancer cell line to study the role of the two main LMW-PTP isoforms, fast and slow, in breast cancer tumorigenesis and migration. Our results show that the siRNAs directed against total LMW-PTP and LMW-PTP slow isoform enhanced cell motility in an invasive breast cancer cell line, MDA-MB-435, with no changes in the proliferation and invasive potential of cells. The total LMW-PTP knockdown caused a more pronounced increase of cell migration. Suppression of total LMW-PTP decreased RhoA activation and suppression of the LMW-PTP slow isoform caused a small but significant increase in RhoA activation. We propose that the increase or decrease in RhoA activation induces changes in stress fibers formation and consequently alter the adhesive and migratory potential of cells. These findings suggest that the two main isoforms of LMW-PTP may act differentially, with the fast isoform having a more prominent role in tumor cell migration. In addition, our results highlight functional specificity among LMW-PTP isoforms, suggesting hitherto unknown roles for these proteins in breast cancer biology. Novel therapeutic approaches targeting LMW-PTP, considering the expression of these two isoforms and not LMW-PTP as a whole, should be investigated.
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影响因子：
3.5
作者：
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