PMID- 25365206 OWN - NLM STAT- MEDLINE DCOM- 20150126 LR - 20230216 IS - 1530-0307 (Electronic) IS - 0023-6837 (Print) IS - 0023-6837 (Linking) VI - 94 IP - 12 DP - 2014 Dec TI - Nestin depletion induces melanoma matrix metalloproteinases and invasion. PG - 1382-95 LID - 10.1038/labinvest.2014.130 [doi] AB - 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. FAU - Lee, Chung-Wei AU - Lee CW AD - Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. FAU - Zhan, Qian AU - Zhan Q AD - Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. FAU - Lezcano, Cecilia AU - Lezcano C AD - Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. FAU - Frank, Markus H AU - Frank MH AD - Transplantation Research Center, Children's Hospital and Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. FAU - Huang, John AU - Huang J AD - 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. FAU - Larson, Allison R AU - Larson AR AD - Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. FAU - Lin, Jennifer Y AU - Lin JY AD - Department of Dermatology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. FAU - Wan, Marilyn T AU - Wan MT AD - 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. FAU - Lin, Ping-I AU - Lin PI AD - Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. FAU - Ma, Jie AU - Ma J AD - Transplantation Research Center, Children's Hospital and Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. FAU - Kleffel, Sonja AU - Kleffel S AD - Department of Dermatology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. FAU - Schatton, Tobias AU - Schatton T AD - Department of Dermatology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. FAU - Lian, Christine G AU - Lian CG AD - Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. FAU - Murphy, George F AU - Murphy GF AD - Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. LA - eng GR - R01 CA113796/CA/NCI NIH HHS/United States GR - T32 AR007098/AR/NIAMS NIH HHS/United States GR - T32 HL007627/HL/NHLBI NIH HHS/United States GR - 5P50CA093683-09/CA/NCI NIH HHS/United States GR - P50 CA093683/CA/NCI NIH HHS/United States GR - I01 RX000989/RX/RRD VA/United States GR - 5T32HL7627-29/HL/NHLBI NIH HHS/United States GR - UL1 TR000170/TR/NCATS NIH HHS/United States GR - R01 CA138231/CA/NCI NIH HHS/United States GR - T32AR007098-38/AR/NIAMS NIH HHS/United States GR - 2T32AR7098-37/AR/NIAMS NIH HHS/United States GR - R01 CA158467/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20141103 PL - United States TA - Lab Invest JT - Laboratory investigation; a journal of technical methods and pathology JID - 0376617 RN - 0 (NES protein, human) RN - 0 (Nestin) RN - 0 (Transforming Growth Factor beta) RN - EC 2.7.10.2 (Focal Adhesion Protein-Tyrosine Kinases) RN - EC 3.4.24.- (Matrix Metalloproteinases) SB - IM MH - Animals MH - Cell Line, Tumor MH - Female MH - Focal Adhesion Protein-Tyrosine Kinases/metabolism MH - Humans MH - Matrix Metalloproteinases/*physiology MH - Melanoma/*pathology MH - Mice MH - Neoplasm Invasiveness MH - Nestin/*physiology MH - Transforming Growth Factor beta/physiology PMC - PMC4419570 MID - NIHMS627037 COIS- Conflict of interest: The authors declare that they have no conflict of interests. EDAT- 2014/11/05 06:00 MHDA- 2015/01/27 06:00 PMCR- 2015/06/01 CRDT- 2014/11/04 06:00 PHST- 2014/05/27 00:00 [received] PHST- 2014/07/25 00:00 [revised] PHST- 2014/09/08 00:00 [accepted] PHST- 2014/11/04 06:00 [entrez] PHST- 2014/11/05 06:00 [pubmed] PHST- 2015/01/27 06:00 [medline] PHST- 2015/06/01 00:00 [pmc-release] AID - S0023-6837(22)00979-5 [pii] AID - 10.1038/labinvest.2014.130 [doi] PST - ppublish SO - Lab Invest. 2014 Dec;94(12):1382-95. doi: 10.1038/labinvest.2014.130. Epub 2014 Nov 3.