Nestin depletion induces melanoma matrix metalloproteinases and invasion
Journal
Laboratory investigation; a journal of technical methods and pathology
Journal Volume
94
Journal Issue
12
Date Issued
2014-12
Author(s)
Lee, Chung-Wei
Zhan, Qian
Lezcano, Cecilia
Frank, Markus H
Larson, Allison R
Lin, Jennifer Y
Wan, Marilyn T
Lin, Ping-I
Ma, Jie
Kleffel, Sonja
Schatton, Tobias
Lian, Christine G
Murphy, George F
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.
Type
journal article