Rodriguez Calleja, L., Jacques, C., Lamoureux, F. et al. (13 more authors) (2016) ΔNp63α silences a microRNA program to aberrantly initiate a wound healing program that promotes TGFβ-induced metastasis. Cancer Research, 76 (11). pp. 3236-3251. ISSN 0008-5472
Abstract
Primary cancer cell dissemination is a key event during the metastatic cascade, but context-specific determinants of this process remain largely undefined. Multiple reports have suggested that the p53 (TP53) family member p63 (TP63) plays an anti-metastatic role through its minor epithelial isoform containing the N-terminal transactivation domain (TAp63). However, the role and contribution of the major p63 isoform lacking this domain, ΔNp63α, remain largely undefined. Here, we report a distinct and TAp63-independent mechanism by which ΔNp63α-expressing cells within a TGFβ-rich microenvironment become positively selected for metastatic dissemination. Orthotopic transplantation of ΔNp63α-expressing human osteosarcoma cells into athymic mice resulted in larger and more frequent lung metastases than transplantation of control cells. Mechanistic investigations revealed that ΔNp63α repressed miR-527 and miR-665, leading to the upregulation of two TGFβ effectors, SMAD4 and TβRII (TGFBR2). Furthermore, we provide evidence that this mechanism reflects a fundamental role for ΔNp63α in the normal wound healing response. We show that ΔNp63α-mediated repression of miR-527/665 controls a TGFβ-dependent signaling node that switches off anti-migratory miR-198 by suppressing the expression of the regulatory factor, KSRP (KHSRP). Collectively, these findings reveal that a novel microRNA network involved in the regulation of physiological wound healing responses is hijacked and suppressed by tumor cells to promote metastatic dissemination.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | ©2016, American Association for Cancer Research. This is an author produced version of a paper subsequently published in Cancer Research. Uploaded in accordance with the publisher's self-archiving policy. |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > The Medical School (Sheffield) > Division of Genomic Medicine (Sheffield) > Department of Oncology and Metabolism (Sheffield) |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 20 Apr 2016 10:47 |
Last Modified: | 18 Jul 2017 03:38 |
Published Version: | http://dx.doi.org/10.1158/0008-5472.CAN-15-2317 |
Status: | Published |
Publisher: | American Association for Cancer Research |
Refereed: | Yes |
Identification Number: | 10.1158/0008-5472.CAN-15-2317 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:98126 |