Nestin depletion induces melanoma matrix metalloproteinases and invasion

Matrix metalloproteinases (MMPs) are key biological mediators of processes as diverse as wound healing, embryogenesis, and cancer progression. Although MMPs may be induced through multiple signaling pathways, the precise mechanisms for their regulation in cancer are incompletely understood. Because...

Descripción completa

Detalles Bibliográficos
Autores principales: Lee, Chung-Wei, Zhan, Qian, Lezcano, Cecilia, Frank, Markus H., Huang, John, Larson, Allison, Lin, Jennifer Y., Wan, Marilyn T., Lin, Ping-I, Ma, Jie, Kleffel, Sonja, Schatton, Tobias, Lian, Christine G., Murphy, George F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4419570/
https://www.ncbi.nlm.nih.gov/pubmed/25365206
http://dx.doi.org/10.1038/labinvest.2014.130
_version_ 1782369603663429632
author Lee, Chung-Wei
Zhan, Qian
Lezcano, Cecilia
Frank, Markus H.
Huang, John
Larson, Allison
Lin, Jennifer Y.
Wan, Marilyn T.
Lin, Ping-I
Ma, Jie
Kleffel, Sonja
Schatton, Tobias
Lian, Christine G.
Murphy, George F.
author_facet Lee, Chung-Wei
Zhan, Qian
Lezcano, Cecilia
Frank, Markus H.
Huang, John
Larson, Allison
Lin, Jennifer Y.
Wan, Marilyn T.
Lin, Ping-I
Ma, Jie
Kleffel, Sonja
Schatton, Tobias
Lian, Christine G.
Murphy, George F.
author_sort Lee, Chung-Wei
collection PubMed
description Matrix metalloproteinases (MMPs) are key biological mediators of processes as diverse as wound healing, embryogenesis, and cancer progression. Although MMPs may be induced through multiple signaling pathways, the precise mechanisms for their regulation in cancer are incompletely understood. Because cytoskeletal changes are known to accompany MMP expression, we sought to examine the potential role of the poorly understood cytoskeletal protein, nestin, in modulating melanoma MMPs. Nestin knockdown (KD) upregulated expression of specific MMPs and MMP-dependent invasion both through extracellular matrix barriers in vitro and in peritumoral connective tissue of xenografts in vivo. Development of 3-dimensionsal melanospheres that in vitro partially recapitulate non-invasive tumorigenic melanoma growth was inhibited by nestin KD, although ECM invasion by aberrant melanospheres that did form was enhanced. Mechanistically, nestin KD-dependent melanoma invasion was associated with intracellular redistribution of phosphorylated focal adhesion kinase (pFAK) and increased melanoma cell responsiveness to transforming growth factor-beta (TGF-β), both implicated in pathways of melanoma invasion. The results suggest that the heretofore poorly understood intermediate filament, nestin, may serve as a novel mediator of MMPs critical to melanoma virulence.
format Online
Article
Text
id pubmed-4419570
institution National Center for Biotechnology Information
language English
publishDate 2014
record_format MEDLINE/PubMed
spelling pubmed-44195702015-06-01 Nestin depletion induces melanoma matrix metalloproteinases and invasion Lee, Chung-Wei Zhan, Qian Lezcano, Cecilia Frank, Markus H. Huang, John Larson, Allison Lin, Jennifer Y. Wan, Marilyn T. Lin, Ping-I Ma, Jie Kleffel, Sonja Schatton, Tobias Lian, Christine G. Murphy, George F. Lab Invest Article Matrix metalloproteinases (MMPs) are key biological mediators of processes as diverse as wound healing, embryogenesis, and cancer progression. Although MMPs may be induced through multiple signaling pathways, the precise mechanisms for their regulation in cancer are incompletely understood. Because cytoskeletal changes are known to accompany MMP expression, we sought to examine the potential role of the poorly understood cytoskeletal protein, nestin, in modulating melanoma MMPs. Nestin knockdown (KD) upregulated expression of specific MMPs and MMP-dependent invasion both through extracellular matrix barriers in vitro and in peritumoral connective tissue of xenografts in vivo. Development of 3-dimensionsal melanospheres that in vitro partially recapitulate non-invasive tumorigenic melanoma growth was inhibited by nestin KD, although ECM invasion by aberrant melanospheres that did form was enhanced. Mechanistically, nestin KD-dependent melanoma invasion was associated with intracellular redistribution of phosphorylated focal adhesion kinase (pFAK) and increased melanoma cell responsiveness to transforming growth factor-beta (TGF-β), both implicated in pathways of melanoma invasion. The results suggest that the heretofore poorly understood intermediate filament, nestin, may serve as a novel mediator of MMPs critical to melanoma virulence. 2014-11-03 2014-12 /pmc/articles/PMC4419570/ /pubmed/25365206 http://dx.doi.org/10.1038/labinvest.2014.130 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Lee, Chung-Wei
Zhan, Qian
Lezcano, Cecilia
Frank, Markus H.
Huang, John
Larson, Allison
Lin, Jennifer Y.
Wan, Marilyn T.
Lin, Ping-I
Ma, Jie
Kleffel, Sonja
Schatton, Tobias
Lian, Christine G.
Murphy, George F.
Nestin depletion induces melanoma matrix metalloproteinases and invasion
title Nestin depletion induces melanoma matrix metalloproteinases and invasion
title_full Nestin depletion induces melanoma matrix metalloproteinases and invasion
title_fullStr Nestin depletion induces melanoma matrix metalloproteinases and invasion
title_full_unstemmed Nestin depletion induces melanoma matrix metalloproteinases and invasion
title_short Nestin depletion induces melanoma matrix metalloproteinases and invasion
title_sort nestin depletion induces melanoma matrix metalloproteinases and invasion
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4419570/
https://www.ncbi.nlm.nih.gov/pubmed/25365206
http://dx.doi.org/10.1038/labinvest.2014.130
work_keys_str_mv AT leechungwei nestindepletioninducesmelanomamatrixmetalloproteinasesandinvasion
AT zhanqian nestindepletioninducesmelanomamatrixmetalloproteinasesandinvasion
AT lezcanocecilia nestindepletioninducesmelanomamatrixmetalloproteinasesandinvasion
AT frankmarkush nestindepletioninducesmelanomamatrixmetalloproteinasesandinvasion
AT huangjohn nestindepletioninducesmelanomamatrixmetalloproteinasesandinvasion
AT larsonallison nestindepletioninducesmelanomamatrixmetalloproteinasesandinvasion
AT linjennifery nestindepletioninducesmelanomamatrixmetalloproteinasesandinvasion
AT wanmarilynt nestindepletioninducesmelanomamatrixmetalloproteinasesandinvasion
AT linpingi nestindepletioninducesmelanomamatrixmetalloproteinasesandinvasion
AT majie nestindepletioninducesmelanomamatrixmetalloproteinasesandinvasion
AT kleffelsonja nestindepletioninducesmelanomamatrixmetalloproteinasesandinvasion
AT schattontobias nestindepletioninducesmelanomamatrixmetalloproteinasesandinvasion
AT lianchristineg nestindepletioninducesmelanomamatrixmetalloproteinasesandinvasion
AT murphygeorgef nestindepletioninducesmelanomamatrixmetalloproteinasesandinvasion