Hsp90ab1 is upregulated in numerous solid tumors, which is thought to induce the angiogenesis and promote cancer metastasis. However, it's actions in gastric cancer (GC) has not been exhibited. In this study, Hsp90ab1 was demonstrated to be overexpressed and correlated with the poor prognosis, proliferation and invasion of GC. Ectopic expression of Hsp90ab1 promoted the proliferation and metastasis of GC cells both in vitro in cell line models of GC and in vivo using two different xenograft mouse models, while opposite effects were observed in Hsp90ab1 silenced cells. Moreover, the underlining molecular mechanism was explored by the co-immunoprecipitation, immunofluorescence, GST pull-down and in vitro ubiquitination assay. Namely, Hsp90ab1 exerted these functions via the interaction of LRP5 and inhibited ubiquitin-mediated degradation of LRP5, an indispensable coreceptor of the Wnt/β-catenin signaling pathway. In addition, the crosstalk between Hsp90ab1 and LRP5 contributed to the upregulation of multiple mesenchymal markers, which are also targets of Wnt/β-catenin. Collectively, this study uncovers the details of the Hsp90ab1-LRP5 axis, providing novel insights into the role and mechanism of invasion and metastasis in GC.

中文翻译：

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Hsp90ab1通过激活AKT和Wnt /β-catenin信号通路在胃癌进展中稳定LRP5，从而促进上皮-间质转化。

Hsp90ab1在许多实体瘤中上调，据认为可诱导血管生成并促进癌症转移。但是，它在胃癌（GC）中的作用尚未展现出来。在这项研究中，Hsp90ab1被证明是过表达的并且与不良的预后，增殖和胃癌的侵袭有关。Hsp90ab1的异位表达在体外和两种不同的异种移植小鼠模型中均在GC细胞系模型和体内促进了GC细胞的增殖和转移，而在Hsp90ab1沉默的细胞中观察到相反的作用。此外，通过共免疫沉淀，免疫荧光，GST下拉和体外泛素化试验探索了分子机制。也就是说，Hsp90ab1通过LRP5的相互作用发挥这些功能，并抑制泛素介导的LRP5降解，Wnt /β-catenin信号通路必不可少的共受体。此外，Hsp90ab1和LRP5之间的串扰导致多个间充质标志物的上调，这些标志物也是Wnt /β-catenin的靶标。总的来说，这项研究揭示了Hsp90ab1-LRP5轴的细节，提供了对GC侵袭和转移的作用和机制的新颖见解。