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    RANK- and c-Met-mediated signal network promotes prostate cancer metastatic colonization

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    Chu, Gina Chia-Yi; Zhau, Haiyen E.; Wang, Ruoxiang; Rogatko, André; Feng, Xu; More... Zayzafoon, Majd; Liu, Youhua; Farach-Carson, Mary C.; You, Sungyong; Kim, Jayoung; Freeman, Michael R.; Chung, Leland W.K. Less...
    Date
    2014
    Abstract
    Prostate cancer (PCa) metastasis to bone is lethal and there is no adequate animal model to study the mechanisms underlying the metastatic process. Here we report that receptor activator of NF-κB ligand (RANKL) expressed by PCa cells consistently induced colonization or metastasis to bone in animal models. RANK-mediated signaling established a premetastatic niche through a feed forward loop, involving the induction of RANKL and c-Met, but repression of androgen receptor (AR) expression and AR signaling pathways. Site-directed mutagenesis and transcription factor deletion/interference assays identified common transcription factor complexes (TFs), c-Myc/Max and AP4, as critical regulatory nodes. RANKL-RANK signaling activated a number of master regulator TFs that control the epithelial-mesenchymal transition (EMT) (Twist1, Slug, Zeb1, Zeb2), stem cell properties (Sox2, Myc, Oct3/4 and Nanog), neuroendocrine differentiation (Sox 9, HIF-1α and FoxA2) and osteomimicry (c-Myc/Max, Sox2, Sox9, HIF1α and Runx2). Abrogating RANK or its downstream c-Myc/Max or c-Met signaling network, minimized or abolished skeletal metastasis in mice. RANKL-expressing LNCaP cells recruited and induced neighboring non-tumorigenic LNCaP cells to express RANKL, c-Met/activated c-Met, while downregulating AR expression. These initially non-tumorigenic cells, once retrieved from the tumors, acquired the potential to colonize and grow in bone. These findings identify a novel mechanism of tumor growth in bone that involves tumor cell reprogramming via RANK-RANKL signaling, as well as a form of signal amplification that mediates recruitment and stable transformation of non-metastatic cells.
    Citation
    Chu, Gina Chia-Yi, Zhau, Haiyen E., Wang, Ruoxiang, et al.. "RANK- and c-Met-mediated signal network promotes prostate cancer metastatic colonization." Endocrine-Related Cancer, 21, (2014) Bioscientifica Ltd.: 311-326. http://dx.doi.org/10.1530/ERC-13-0548.
    Published Version
    http://dx.doi.org/10.1530/ERC-13-0548
    Keyword
    RANKL; RANK; c-Met; prostate cancer; metastasis; More... cancer dormancy Less...
    Type
    Journal article
    Publisher
    Bioscientifica Ltd.
    Citable link to this page
    https://hdl.handle.net/1911/77501
    Rights
    This work is licensed under a Creative Commons Attribution 3.0 Unported License.
    Link to License
    https://creativecommons.org/licenses/by/3.0/
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    • Biochemistry and Cell Biology Publications [118]
    • Faculty Publications [4988]

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    Home | FAQ | Contact Us | Privacy Notice | Accessibility Statement
    Managed by the Digital Scholarship Services at Fondren Library, Rice University
    Physical Address: 6100 Main Street, Houston, Texas 77005
    Mailing Address: MS-44, P.O.BOX 1892, Houston, Texas 77251-1892
    Site Map