Rewiring of an epithelial differentiation factor, miR-203, to inhibit human squamous cell carcinoma metastasis

Nathan Benaich; Samuel Woodhouse; Stephen J Goldie; Ajay Mishra; Sven R Quist; Fiona M Watt

doi:10.1016/j.celrep.2014.08.062

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.

Authors

Nathan Benaich¹, Samuel Woodhouse², Stephen J Goldie³, Ajay Mishra², Sven R Quist⁴, Fiona M Watt⁵

Affiliations

¹ Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK; Centre for Stem Cells and Regenerative Medicine, King's College London, 28(th) Floor, Tower Wing, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
² Centre for Stem Cells and Regenerative Medicine, King's College London, 28(th) Floor, Tower Wing, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
³ Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
⁴ Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK; Clinic of Dermatology and Venereology, Otto-von-Guericke University, Magdeburg, Leipziger Strasse 44, 39120 Magdeburg, Germany.
⁵ Centre for Stem Cells and Regenerative Medicine, King's College London, 28(th) Floor, Tower Wing, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK. Electronic address: fiona.watt@kcl.ac.uk.

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

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding