title: Nestin depletion induces melanoma matrix metalloproteinases and invasion.
abstract: 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 the expression of specific MMPs and MMP-dependent invasion both through extracellular matrix barriers in vitro and in peritumoral connective tissue of xenografts in vivo. The development of three-dimensional melanospheres that in vitro partially recapitulate noninvasive 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 and increased melanoma cell responsiveness to transforming growth factor-beta, 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.
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Chung-Wei
authors.initials: CW
authors.lastname: Lee
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhan
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Lezcano
authors.affiliation: Transplantation Research Center, Children's Hospital and Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Markus H
authors.initials: MH
authors.lastname: Frank
authors.affiliation: 1] Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA [2] Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: John
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Allison R
authors.initials: AR
authors.lastname: Larson
authors.affiliation: Department of Dermatology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Jennifer Y
authors.initials: JY
authors.lastname: Lin
authors.affiliation: 1] Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA [2] Department of Dermatology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Marilyn T
authors.initials: MT
authors.lastname: Wan
authors.affiliation: Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Ping-I
authors.initials: PI
authors.lastname: Lin
authors.affiliation: Transplantation Research Center, Children's Hospital and Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Dermatology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Sonja
authors.initials: S
authors.lastname: Kleffel
authors.affiliation: Department of Dermatology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Tobias
authors.initials: T
authors.lastname: Schatton
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Christine G
authors.initials: CG
authors.lastname: Lian
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: George F
authors.initials: GF
authors.lastname: Murphy
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D006801:Humans; D020782:Matrix Metalloproteinases / Q000502:physiology*; D008545:Melanoma / Q000473:pathology*; D051379:Mice; D009361:Neoplasm Invasiveness; D064231:Nestin / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology
chemical_list: C577484:NES protein, human; D064231:Nestin; D016212:Transforming Growth Factor beta; D051416:Focal Adhesion Protein-Tyrosine Kinases; D020782:Matrix Metalloproteinases