WLS inhibits melanoma cell proliferation through the β‐catenin signalling pathway and induces spontaneous metastasis
| Autor: | Pei-Tzu Yang, Jamie N. Anastas, Michi M. Shinohara, Anja K. Bosserhoff, Rachel A. Toroni, Andy J. Chien, Jamie M. Goodson, Randall T. Moon |
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| Rok vydání: | 2012 |
| Předmět: |
Lung Neoplasms
Skin Neoplasms Beta-catenin Transplantation Heterologous Biology Mice 03 medical and health sciences 0302 clinical medicine Cell Movement Cell Line Tumor melanoma medicine Animals Humans Research Articles beta Catenin Cell Proliferation 030304 developmental biology WNTLESS 0303 health sciences Cell growth Melanoma WNT secretion Intracellular Signaling Peptides and Proteins Wnt signaling pathway beta-catenin Catenins Cell migration medicine.disease spontaneous metastasis Hedgehog signaling pathway 3. Good health Cell biology Wnt Proteins 030220 oncology & carcinogenesis Catenin biology.protein Molecular Medicine Signal transduction Signal Transduction |
| Zdroj: | EMBO Molecular Medicine |
| ISSN: | 1757-4684 1757-4676 |
| Popis: | Elevated levels of nuclear β-catenin are associated with higher rates of survival in patients with melanoma, raising questions as to how ß-catenin is regulated in this context. In the present study, we investigated the formal possibility that the secretion of WNT ligands that stabilize ß-catenin may be regulated in melanoma and thus contributes to differences in ß-catenin levels. We find that WLS, a conserved transmembrane protein necessary for WNT secretion, is decreased in both melanoma cell lines and in patient tumours relative to skin and to benign nevi. Unexpectedly, reducing endogenous WLS with shRNAs in human melanoma cell lines promotes spontaneous lung metastasis in xenografts in mice and promotes cell proliferation in vitro. Conversely, overexpression of WLS inhibits cell proliferation in vitro. Activating β-catenin downstream of WNT secretion blocks the increased cell migration and proliferation observed in the presence of WLS shRNAs, while inhibiting WNT signalling rescues the growth defects induced by excess WLS. These data suggest that WLS functions as a negative regulator of melanoma proliferation and spontaneous metastasis by activating WNT/β-catenin signalling. |
| Databáze: | OpenAIRE |
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