Abstract |
Tumor progression and metastasis are the major causes of death among cancer associated mortality. Metastatic cells acquire features of migration and invasion and usually undergo epithelia-mesenchymal transition (EMT). Acquirement of these various hallmarks rely on different cellular pathways, including TGF-β and Wnt signaling. Recently, we reported that WW domain-containing oxidoreductase (WWOX) acts as a tumor suppressor and has anti-metastatic activities involving regulation of several key microRNAs ( miRNAs) in triple-negative breast cancer (TNBC). Here, we report that WWOX restoration in highly metastatic MDA-MB435S cancer cells alters mRNA expression profiles; further, WWOX interacts with various proteins to exert its tumor suppressor function. Careful alignment and analysis of gene and miRNA expression in these cells revealed profound changes in cellular pathways mediating adhesion, invasion and motility. We further demonstrate that WWOX, through regulation of miR-146a levels, regulates SMAD3, which is a member of the TGF-β signaling pathway. Moreover, proteomic analysis of WWOX partners revealed regulation of the Wnt-signaling activation through physical interaction with Disheveled. Altogether, these findings underscore a significant role for WWOX in antagonizing metastasis, further highlighting its role and therapeutic potential in suppressing tumor progression.
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Authors | Saleh Khawaled, Giovanni Nigita, Rosario Distefano, Sara Oster, Sung-Suk Suh, Yoav Smith, Abed Khalaileh, Yong Peng, Carlo M Croce, Tamar Geiger, Victoria L Seewaldt, Rami I Aqeilan |
Journal | Signal transduction and targeted therapy
(Signal Transduct Target Ther)
Vol. 5
Issue 1
Pg. 43
(04 17 2020)
ISSN: 2059-3635 [Electronic] England |
PMID | 32300104
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- DVL1 protein, human
- Dishevelled Proteins
- MIRN146 microRNA, human
- MicroRNAs
- SMAD3 protein, human
- Smad3 Protein
- Transforming Growth Factor beta
- Tumor Suppressor Proteins
- WW Domain-Containing Oxidoreductase
- WWOX protein, human
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Topics |
- Cell Movement
(genetics)
- Cell Proliferation
(genetics)
- Dishevelled Proteins
(genetics)
- Epithelial-Mesenchymal Transition
(genetics)
- Female
- Gene Expression Regulation, Neoplastic
(genetics)
- Genetic Pleiotropy
(genetics)
- Humans
- MicroRNAs
(genetics)
- Neoplasm Metastasis
- Protein Interaction Maps
(genetics)
- Signal Transduction
(genetics)
- Smad3 Protein
(genetics)
- Transforming Growth Factor beta
(genetics)
- Triple Negative Breast Neoplasms
(genetics, pathology)
- Tumor Suppressor Proteins
(genetics)
- WW Domain-Containing Oxidoreductase
(genetics)
- Wnt Signaling Pathway
(genetics)
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