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WLS inhibits melanoma cell proliferation through the β‐catenin signalling pathway and induces spontaneous metastasis

Pei‐Tzu Yang, Jamie N. Anastas, Rachel A. Toroni, Michi M. Shinohara, Jamie M. Goodson, Anja K. Bosserhoff, Andy J. Chien, Randall T. Moon

Author Affiliations

  1. Pei‐Tzu Yang1,
  2. Jamie N. Anastas1,
  3. Rachel A. Toroni2,
  4. Michi M. Shinohara2,
  5. Jamie M. Goodson3,
  6. Anja K. Bosserhoff4,
  7. Andy J. Chien1,2 and
  8. Randall T. Moon (rtmoon{at}uw.edu) *,1
  1. 1Department of Pharmacology, Howard Hughes Medical Institute, Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA, USA
  2. 2Division of Dermatology, Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA
  3. 3Department of Biology, University of Washington, Seattle, WA, USA
  4. 4Department of Pathology, University of Regensburg, Regensburg, Germany
  1. *Tel: +1 206 543 1722; Fax: +1 206 543 1183
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Abstract

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.

  • Received April 19, 2012.
  • Revision received September 20, 2012.
  • Accepted September 24, 2012.
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This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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