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      miR-375 Regulates Invasion-Related Proteins Vimentin and L-Plastin.

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          Abstract

          Invasion is a hallmark of advanced head and neck squamous cell carcinoma (HNSCC). We previously determined that low relative miR-375 expression was associated with poor patient prognosis. HNSCC cells with increased miR-375 expression have lower invasive properties and impaired invadopodium activity. Using stable isotope labeling with amino acids in cell culture and reverse-phase liquid chromatography mass spectrometry, we assessed the impact of miR-375 expression on protein levels in UM-SCC-1 cells. Increased miR-375 expression was associated with down-regulation of proteins involved in cellular assembly and organization, death and survival, and movement. Two invasion-associated proteins, vimentin and L-plastin, were strongly down-regulated by miR-375. Luciferase reporter assays demonstrated that high miR-375 expression reduced vimentin promoter activity, suggesting that vimentin is an indirect target of miR-375. Runt-related transcription factor 1 (RUNX1) is a potential miR-375 direct target, and its knockdown reduced vimentin and L-plastin expression. Data in The Cancer Genome Atlas HNSCC database showed a significant inverse correlation between miR-375 expression and RUNX1, vimentin, and L-plastin RNA expression. These clinical correlations validate our in vitro model findings and support a mechanism in which miR-375 suppresses RUNX1 levels, resulting in reduced vimentin and L-plastin expression. Furthermore, knockdown of RUNX1, L-plastin, and vimentin resulted in significant reductions in cell invasion in vitro, indicating the functional significance of miR-375 regulation of specific proteins involved in HNSCC invasion.

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          Author and article information

          Journal
          Am. J. Pathol.
          The American journal of pathology
          Elsevier BV
          1525-2191
          0002-9440
          May 10 2017
          Affiliations
          [1 ] Department of Pathology, Albert Einstein College of Medicine, Bronx, New York; Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, New York.
          [2 ] Department of Pathology, Albert Einstein College of Medicine, Bronx, New York; Laboratory for Macromolecular Analysis and Proteomics, Albert Einstein College of Medicine, Bronx, New York.
          [3 ] Laboratory for Macromolecular Analysis and Proteomics, Albert Einstein College of Medicine, Bronx, New York.
          [4 ] Department of Pathology, Albert Einstein College of Medicine, Bronx, New York.
          [5 ] Department of Pathology, Albert Einstein College of Medicine, Bronx, New York; Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, New York. Electronic address: jeffrey.segall@einstein.yu.edu.
          Article
          S0002-9440(17)30205-5
          10.1016/j.ajpath.2017.02.019
          28499703

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