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首页> 外文期刊>Journal of experimental & clinical cancer research : >HSP90-dependent PUS7 overexpression facilitates the metastasis of colorectal cancer cells by regulating LASP1 abundance
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HSP90-dependent PUS7 overexpression facilitates the metastasis of colorectal cancer cells by regulating LASP1 abundance

机译：HSP90依赖性PUS7过表达通过调节Lasp1丰度来促进结肠直肠癌细胞转移

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Pseudouridine synthase (PUS) 7 is a member of the PUS family that catalyses pseudouridine formation. It has been shown to be involved in intellectual development and haematological malignancies. Nevertheless, the role and the underlying molecular mechanisms of PUS7 in solid tumours, such as colorectal cancer (CRC), remain unexplored. This study elucidated, for the first time, the role of PUS7 in CRC cell metastasis and the underlying mechanisms. We conducted immunohistochemistry, qPCR, and western blotting to quantify the expression of PUS7 in CRC tissues as well as cell lines. Besides, diverse in vivo and in vitro functional tests were employed to establish the function of PUS7 in CRC. RNA-seq and proteome profiling analysis were also applied to identify the targets of PUS7. PUS7-interacting proteins were further uncovered using immunoprecipitation and mass spectrometry. Overexpression of PUS7 was observed in CRC tissues and was linked to advanced clinical stages and shorter overall survival. PUS7 silencing effectively repressed CRC cell metastasis, while its upregulation promoted metastasis, independently of the PUS7 catalytic activity. LASP1 was identified as a downstream effector of PUS7. Forced LASP1 expression abolished the metastasis suppression triggered by PUS7 silencing. Furthermore, HSP90 was identified as a client protein of PUS7, associated with the increased PUS7 abundance in CRC. NMS-E973, a specific HSP90 inhibitor, also showed higher anti-metastatic activity when combined with PUS7 repression. Importantly, in line with these results, in human CRC tissues, the expression of PUS7 was positively linked to the expression of HSP90 and LASP1, and patients co-expressing HSP90/PUS7/LASP1 showed a worse prognosis. The HSP90-dependent PUS7 upregulation promotes CRC cell metastasis via the regulation of LASP1. Thus, targeting the HSP90/PUS7/LASP1 axis may be a novel approach for the treatment of CRC.
机译：假尿素合酶（PUS）7是催化拷贝的PUS系列的成员。已显示涉及智力发育和血液恶性肿瘤。然而，PUS7在实体瘤中的作用和潜在的分子机制如结肠直肠癌（CRC），仍未开发。本研究阐述了PUS7在CRC细胞转移和潜在机制中的作用。我们进行了免疫组织化学，QPCR和Western印迹，以量化CRC组织中PUS7的表达以及细胞系。此外，使用体内和体外功能测试的不同，以建立CRC中PUS7的功能。还应用RNA-SEQ和蛋白质组分析分析以鉴定PUS7的靶标。使用免疫沉淀和质谱法进一步发现PUS7相互作用蛋白。在CRC组织中观察到PUS7的过度表达，并与晚期临床阶段相关联，并且整体存活较短。 PUS7沉默有效地压抑了CRC细胞转移，而其上调促进转移，独立于PUS7催化活性。 Lap1被鉴定为PUS7的下游效应器。强制LASP1表达废除了PUS7沉默触发的转移抑制。此外，HSP90被鉴定为PUS7的客户蛋白，与CRC中的PUS7丰度增加相关。 NMS-E973，一种特异性HSP90抑制剂，当与PUS7抑制结合时，也显示出更高的抗转移性活动。重要的是，根据这些结果，在人CRC组织中，PUS7的表达与Hsp90和Lasp1的表达呈正相关，并且共同表达HSP90 / PUS7 / LASP1的患者的预后表现出更差。 HSP90依赖性PUS7上调通过LAP1的调节促进CRC细胞转移。因此，靶向HSP90 / PUS7 / LASP1轴可以是用于治疗CRC的新方法。

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