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Huang G.,Shanghai University | Li L.,Clinical and Translational Research Center Shanghai East Hospital | Li L.,Tongji University | Zhou W.,Shanghai University
Oncology Reports | Year: 2015

To elucidate the molecular mechanisms underlying the pathogenesis and treatment of human primary hepatocellular carcinoma (HCC), it is important to explore novel HCC-associated genes. In the present study, we examined the expression of ubiquitin-specific peptidase 14 (USP14) in patients with HCC using quantitative PCR and immunohistochemical techniques. The expression of USP14 in tumor tissues of patients with HCC was significantly higher than that in adjacent non-cancerous and normal liver tissues. It was also determined whether the expression profile of USP14 was associated with the clinical characteristics of HCC. Increased USP14 expression was associated with some clinicopathological variables, such as advancing tumor stage. A Kaplan-Meier curve analysis demonstrated that patients with HCC having a high USP14 expression had a significantly poorer prognosis after surgery than patients with lower USP14 expression levels. Knockdown of USP14 with the lentiviral vector delivery of shRNA in human hepatocarcinoma SMMC7721 cells suppressed cell proliferation, altered the cell cycle and induced cell apoptosis. Additionally, the Wnt/β-catenin pathway was activated in HCC patients with USP14 overexpression. These findings strongly suggested that USP14 activation plays an oncogenic role in promoting tumor progression in HCC. Thus, our findings suggested that USP14 is involved in the progression of HCC and may be a useful therapeutic target in HCC. These findings likely reflect the key role that USP14 plays in the pathogenesis of HCC. Therefore, the identification of USP14 and USP14-driven genes may promote the investigation of its functional role to develop more effective therapies for HCC, especially advanced HCC. Source

Chen J.,Tongji University | Yan H.,Tongji University | Ren D.-N.,Clinical and Translational Research Center Shanghai East Hospital | Yin Y.,Clinical and Translational Research Center Shanghai East Hospital | And 11 more authors.
Cellular Signalling | Year: 2014

Canonical Wnt/β-catenin signaling pathway plays important roles in multiple aspects of cellular responses in development and diseases. It is currently thought that Wnt receptor Frizzled (Frz) exists separately to Wnt coreceptors LRP5 and LRP6 (LRP5/6), and that Wnt-Frz-LRP5/6 triple complex formation bridged by Wnt ligand is needed for canonical pathway activation. We recently showed that Frz and LRP5/6 interact with each other in the absence of Wnt ligand binding and this interaction maintains the Frz-LRP5/6 complex in an inactive state. Here, we further show that Wnt ligand stimulation induces conformational change of the Frz-LRP6 complex and leads to hexamer formation containing the core LDLR domain-mediated LRP6 homodimer that is stabilized by two pairs of Wnt3a and Frz8, that is, Wnt3a-Frz8 LRP6-LRP6-Frz8-Wnt3a. This LDLR-mediated LRP6 dimerization is essential for robust canonical Wnt pathway activation. Our study thus suggests a previously unrecognized mode of receptor interaction in Wnt signal initiation. © 2014 Elsevier Inc. Source

Ren D.-N.,Clinical and Translational Research Center Shanghai East Hospital | Chen J.,Tongji University | Li Z.,Chiba University | Yan H.,Tongji University | And 19 more authors.
Nature Communications | Year: 2015

How Wnt signalling including canonical and non-canonical pathways are initiated at the cell surface is not completely understood. Here we report that Wnt receptor Frizzled (Frz) and theco-receptors LRP5 and LRP6 (LRP5/6) directly interact with each other and this interaction is regulated by the LRP6 ectodomain. Importantly, through direct binding to Frz, LRP5/6 are able to prevent Frz-regulated non-canonical pathway activation and further non-canonical pathway-mediated tumour metastasis. Knockdown of endogenous LRP5/6 promotes otherwise-nonaggressive tumour cells to migrate in vitro, whereas a soluble recombinant protein of LRP6 ectodomain suppresses migration and metastasis of otherwise-aggressive tumour cells in vitro and in vivo. Furthermore, the expression level of membrane LRP5/6 correlates inversely with metastasis in mouse and human breast cancer. Our study suggests a previously unrecognized mode of receptor interaction, revealing the mechanism of LRP5/6 in inhibition of non-canonical pathway, and a possible clinical use of the LRP6 ectodomain to impede metastasis. © 2015 Macmillan Publishers Limited. All rights reserved. Source

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