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

Lizandra Jimenez, Jihyeon Lim, Berta Burd, Thomas M. Harris, Thomas J. Ow, Nicole Kawachi, Thomas J. Belbin, Ruth Angeletti, Michael B. Prystowsky, Geoffrey Childs, Jeffrey E. Segall

Research output: Contribution to journalArticle

2 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1523-1536
Number of pages14
JournalAmerican Journal of Pathology
Volume187
Issue number7
DOIs
StatePublished - Jul 2017

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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