Hsp90ab1 stabilizes LRP5 to promote epithelial-mesenchymal transition via activating of AKT and Wnt/β-catenin signaling pathways in gastric cancer progression

• Published in: Oncogene Vol. 38; no. 9; pp. 1489 - 1507
• Main Authors: Wang, Huanan, Deng, Guangxu, Ai, Meiling, Xu, Zhijun, Mou, Tingyu, Yu, Jiang, Liu, Hao, Wang, Shuang, Li, Guoxin
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.02.2019; Nature Publishing Group UK
• Subjects: AKT protein; Angiogenesis; Animal models; Animals; beta Catenin - genetics; Cell culture; Cell Line, Tumor; Cell proliferation; Cell Proliferation - genetics; Disease Progression; Ectopic expression; Epithelial-Mesenchymal Transition - genetics; Gastric cancer; Gene Expression Regulation, Neoplastic; HSP90 Heat-Shock Proteins - genetics; Humans; Immunofluorescence; Immunoprecipitation; Kinases; Low Density Lipoprotein Receptor-Related Protein-5 - genetics; LRP5 protein; Mesenchyme; Metastases; Metastasis; Mice; Proto-Oncogene Proteins c-akt - genetics; Signal transduction; Solid tumors; Stomach Neoplasms - genetics; Stomach Neoplasms - pathology; Ubiquitin; Ubiquitination; Wnt protein; Wnt Signaling Pathway - drug effects; Xenografts; β-Catenin
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-018-0532-5

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.