RNAi knockdown of Hop (Hsp70/Hsp90 organising protein) decreases invasion via MMP-2 down regulation
RNAi knockdown of Hop (Hsp70/Hsp90 organising protein) decreases invasion via MMP-2 down regulation
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DOI：
10.1016/j.canlet.2011.03.004
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发表时间：
2011-07-28
期刊：
影响因子：
9.7
通讯作者：
Clynes, Martin
中科院分区：
文献类型：
--
作者：
Walsh, Naomi;Larkin, AnneMarie;Clynes, Martin
我们之前在浸润性胰腺癌细胞系和胰腺癌患者的恶性组织中发现Hop过表达，提示Hop在浸润性胰腺癌的生物学中具有重要作用。Hop是一种与Hsp70/Hsp90结合的共伴侣蛋白。我们假设，通过靶向Hop，可能会改变包括hsp90依赖复合物在内的调节入侵和客户蛋白稳定的信号通路。在这项研究中，我们发现小干扰（si）RNA敲低Hop可减少胰腺癌细胞的侵袭，导致下游靶基因基质金属蛋白酶-2 （MMP-2）的表达降低。条件培养基中的Hop与MMP-2共同免疫沉淀，暗示Hop可能具有细胞外功能。敲低Hop表达也降低了Hsp90客户蛋白、HER2、Bcr-Abl、c-MET和v-Src的表达水平。此外，与低级别PanIN相比，Hop在高级别PanINs中强烈表达，在浸润性导管胰腺癌中表现出不同的定位，表明Hop的定位是胰腺肿瘤的重要因素。我们的数据表明，Hop表达的衰减使关键信号转导蛋白失活，可能通过调节Hsp90活性来降低胰腺癌细胞的侵袭性。因此，在胰腺癌中靶向Hop可能是一种可行的癌症靶向治疗策略。2011爱思唯尔爱尔兰有限公司版权所有。
We previously identified Hop as over expressed in invasive pancreatic cancer cell lines and malignant tissues of pancreatic cancer patients, suggesting an important role for Hop in the biology of invasive pancreatic cancer. Hop is a co-chaperone protein that binds to both Hsp70/Hsp90. We hypothesised that by targeting Hop, signalling pathways modulating invasion and client protein stabilisation involving Hsp90-dependent complexes may be altered.In this study, we show that Hop knockdown by small interfering (si)RNA reduces the invasion of pancreatic cancer cells, resulting in decreased expression of the downstream target gene, matrix metalloproteinases-2 (MMP-2). Hop in conditioned media co-immunoprecipitates with MMP-2, implicating a possible extracellular function for Hop. Knockdown of Hop expression also reduced expression levels of Hsp90 client proteins, HER2, Bcr-Abl, c-MET and v-Src. Furthermore, Hop is strongly expressed in high grade PanINs compared to lower PanIN grades, displaying differential localisation in invasive ductal pancreatic cancer, indicating that the localisation of Hop is an important factor in pancreatic tumours.Our data suggests that the attenuation of Hop expression inactivates key signal transduction proteins which may decrease the invasiveness of pancreatic cancer cells possibly through the modulation of Hsp90 activity. Therefore, targeting Hop in pancreatic cancer may constitute a viable strategy for targeted cancer therapy. (C) 2011 Elsevier Ireland Ltd. All rights reserved.