Rewiring of an Epithelial Differentiation Factor, miR-203, to Inhibit Human Squamous Cell Carcinoma Metastasis

Cell Rep. 2014 Oct 9;9(1):104-117. doi: 10.1016/j.celrep.2014.08.062. Epub 2014 Oct 2.

Abstract

Metastatic colonization of distant organs underpins the majority of human-cancer-related deaths, including deaths from head and neck squamous cell carcinoma (HNSCC). We report that miR-203, a miRNA that triggers differentiation in multilayered epithelia, inhibits multiple postextravasation events during HNSCC lung metastasis. Inducible reactivation of miR-203 in already established lung metastases reduces the overall metastatic burden. Using an integrated approach, we reveal that miR-203 inhibits metastasis independently of its effects on differentiation. In vivo genetic reconstitution experiments show that miR-203 inhibits lung metastasis by suppressing the prometastatic activities of three factors involved in cytoskeletal dynamics (LASP1), extracellular matrix remodeling (SPARC), and cell metabolism (NUAK1). Expression of miR-203 and its downstream effectors correlates with HNSCC overall survival outcomes, indicating the therapeutic potential of targeting this signaling axis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / antagonists & inhibitors
  • Animals
  • Carcinoma, Squamous Cell / genetics*
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / pathology*
  • Cell Differentiation / genetics
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Cytoskeletal Proteins / antagonists & inhibitors
  • Head and Neck Neoplasms / genetics*
  • Head and Neck Neoplasms / metabolism
  • Head and Neck Neoplasms / pathology*
  • Heterografts
  • Humans
  • LIM Domain Proteins / antagonists & inhibitors
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / prevention & control*
  • Lung Neoplasms / secondary*
  • Mice
  • MicroRNAs / genetics*
  • Neoplasm Metastasis
  • Osteonectin / antagonists & inhibitors
  • Prognosis
  • Protein Kinases
  • Repressor Proteins / antagonists & inhibitors
  • Signal Transduction
  • Squamous Cell Carcinoma of Head and Neck

Substances

  • Adaptor Proteins, Signal Transducing
  • Cytoskeletal Proteins
  • LASP1 protein, human
  • LIM Domain Proteins
  • MIRN203 microRNA, human
  • MicroRNAs
  • Osteonectin
  • Repressor Proteins
  • SPARC protein, human
  • Protein Kinases
  • NUAK1 protein, human

Associated data

  • GEO/GSE47028